Full text data of H3F3A
H3F3A
(H3.3B)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Histone H3.3
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Histone H3.3
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P84243
ID H33_HUMAN Reviewed; 136 AA.
AC P84243; P06351; P33155; Q5VV55; Q5VV56; Q66I33; Q9V3W4;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 107.
DE RecName: Full=Histone H3.3;
GN Name=H3F3A; Synonyms=H3.3A, H3F3; ORFNames=PP781;
GN and
GN Name=H3F3B; Synonyms=H3.3B;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (H3F3A).
RC TISSUE=Fibroblast;
RX PubMed=2859593; DOI=10.1073/pnas.82.9.2834;
RA Wells D., Kedes L.;
RT "Structure of a human histone cDNA: evidence that basally expressed
RT histone genes have intervening sequences and encode polyadenylylated
RT mRNAs.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:2834-2838(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (H3F3A).
RX PubMed=3031613; DOI=10.1093/nar/15.7.2871;
RA Wells D., Hoffman D., Kedes L.;
RT "Unusual structure, evolutionary conservation of non-coding sequences
RT and numerous pseudogenes characterize the human H3.3 histone multigene
RT family.";
RL Nucleic Acids Res. 15:2871-2889(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (H3F3B).
RC TISSUE=Testis;
RX PubMed=8586426; DOI=10.1006/geno.1995.9878;
RA Albig W., Bramlage B., Gruber K., Klobeck H.-G., Kunz J., Doenecke D.;
RT "The human replacement histone H3.3B gene (H3F3B).";
RL Genomics 30:264-272(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15498874; DOI=10.1073/pnas.0404089101;
RA Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H.,
RA Qiu X., Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y.,
RA Shu H., Chen X., Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S.,
RA Gu J.;
RT "Large-scale cDNA transfection screening for genes related to cancer
RT development and progression.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (H3F3B).
RC TISSUE=Retina;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (H3F3A AND H3F3B).
RC TISSUE=Bone marrow, Brain, Colon, Eye, Lung, Muscle, Spinal cord,
RC Testis, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP PARTIAL PROTEIN SEQUENCE, METHYLATION AT LYS-10; LYS-28 AND LYS-37,
RP AND ACETYLATION AT LYS-15 AND LYS-24.
RX PubMed=7309716;
RA Ohe Y., Iwai K.;
RT "Human spleen histone H3. Isolation and amino acid sequence.";
RL J. Biochem. 90:1205-1211(1981).
RN [9]
RP PROTEIN SEQUENCE OF 28-41, METHYLATION AT LYS-5; LYS-10; LYS-28 AND
RP LYS-37, PHOSPHORYLATION AT THR-4; SER-11; SER-29 AND SER-32,
RP ACETYLATION AT LYS-10 AND LYS-15, AND MASS SPECTROMETRY.
RX PubMed=16185088; DOI=10.1021/bi050906n;
RA Garcia B.A., Barber C.M., Hake S.B., Ptak C., Turner F.B., Busby S.A.,
RA Shabanowitz J., Moran R.G., Allis C.D., Hunt D.F.;
RT "Modifications of human histone H3 variants during mitosis.";
RL Biochemistry 44:13202-13213(2005).
RN [10]
RP PROTEIN SEQUENCE OF 58-64; 117-120 AND 124-135, AND PHOSPHORYLATION AT
RP SER-11 AND SER-29.
RX PubMed=10464286; DOI=10.1074/jbc.274.36.25543;
RA Goto H., Tomono Y., Ajiro K., Kosako H., Fujita M., Sakurai M.,
RA Okawa K., Iwamatsu A., Okigaki T., Takahashi T., Inagaki M.;
RT "Identification of a novel phosphorylation site on histone H3 coupled
RT with mitotic chromosome condensation.";
RL J. Biol. Chem. 274:25543-25549(1999).
RN [11]
RP METHYLATION AT LYS-10.
RX PubMed=11242053; DOI=10.1038/35065132;
RA Lachner M., O'Carroll D., Rea S., Mechtler K., Jenuwein T.;
RT "Methylation of histone H3 lysine 9 creates a binding site for HP1
RT proteins.";
RL Nature 410:116-120(2001).
RN [12]
RP PHOSPHORYLATION AT SER-11 AND SER-29.
RX PubMed=11856369; DOI=10.1046/j.1356-9597.2001.00498.x;
RA Goto H., Yasui Y., Nigg E.A., Inagaki M.;
RT "Aurora-B phosphorylates Histone H3 at serine28 with regard to the
RT mitotic chromosome condensation.";
RL Genes Cells 7:11-17(2002).
RN [13]
RP PHOSPHORYLATION AT SER-11 AND THR-12.
RX PubMed=12560483; DOI=10.1093/nar/gkg176;
RA Preuss U., Landsberg G., Scheidtmann K.H.;
RT "Novel mitosis-specific phosphorylation of histone H3 at Thr11
RT mediated by Dlk/ZIP kinase.";
RL Nucleic Acids Res. 31:878-885(2003).
RN [14]
RP FUNCTION, AND INTERACTION WITH HIRA.
RX PubMed=14718166; DOI=10.1016/S0092-8674(03)01064-X;
RA Tagami H., Ray-Gallet D., Almouzni G., Nakatani Y.;
RT "Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways
RT dependent or independent of DNA synthesis.";
RL Cell 116:51-61(2004).
RN [15]
RP METHYLATION AT ARG-18.
RX PubMed=15471871; DOI=10.1074/jbc.M410021200;
RA Ananthanarayanan M., Li S., Balasubramaniyan N., Suchy F.J.,
RA Walsh M.J.;
RT "Ligand-dependent activation of the farnesoid X-receptor directs
RT arginine methylation of histone H3 by CARM1.";
RL J. Biol. Chem. 279:54348-54357(2004).
RN [16]
RP METHYLATION AT LYS-80.
RX PubMed=15525939; DOI=10.1038/nature03114;
RA Huyen Y., Zgheib O., Ditullio R.A. Jr., Gorgoulis V.G., Zacharatos P.,
RA Petty T.J., Sheston E.A., Mellert H.S., Stavridi E.S.,
RA Halazonetis T.D.;
RT "Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand
RT breaks.";
RL Nature 432:406-411(2004).
RN [17]
RP CITRULLINATION AT ARG-9 AND ARG-18, AND METHYLATION AT ARG-18.
RX PubMed=15345777; DOI=10.1126/science.1101400;
RA Wang Y., Wysocka J., Sayegh J., Lee Y.-H., Perlin J.R., Leonelli L.,
RA Sonbuchner L.S., McDonald C.H., Cook R.G., Dou Y., Roeder R.G.,
RA Clarke S., Stallcup M.R., Allis C.D., Coonrod S.A.;
RT "Human PAD4 regulates histone arginine methylation levels via
RT demethylimination.";
RL Science 306:279-283(2004).
RN [18]
RP FUNCTION.
RX PubMed=15776021; DOI=10.1038/sj.embor.7400366;
RA Chow C.-M., Georgiou A., Szutorisz H., Maia e Silva A., Pombo A.,
RA Barahona I., Dargelos E., Canzonetta C., Dillon N.;
RT "Variant histone H3.3 marks promoters of transcriptionally active
RT genes during mammalian cell division.";
RL EMBO Rep. 6:354-360(2005).
RN [19]
RP PHOSPHORYLATION AT THR-4; SER-11 AND SER-29.
RX PubMed=15681610; DOI=10.1101/gad.1267105;
RA Dai J., Sultan S., Taylor S.S., Higgins J.M.G.;
RT "The kinase haspin is required for mitotic histone H3 Thr 3
RT phosphorylation and normal metaphase chromosome alignment.";
RL Genes Dev. 19:472-488(2005).
RN [20]
RP PHOSPHORYLATION AT SER-29.
RX PubMed=15684425; DOI=10.1074/jbc.M410521200;
RA Choi H.S., Choi B.Y., Cho Y.-Y., Zhu F., Bode A.M., Dong Z.;
RT "Phosphorylation of Ser28 in histone H3 mediated by mixed lineage
RT kinase-like mitogen-activated protein triple kinase alpha.";
RL J. Biol. Chem. 280:13545-13553(2005).
RN [21]
RP PHOSPHORYLATION AT SER-11; SER-29 AND SER-32, AND MASS SPECTROMETRY.
RX PubMed=15851689; DOI=10.1073/pnas.0502413102;
RA Hake S.B., Garcia B.A., Kauer M., Baker S.P., Shabanowitz J.,
RA Hunt D.F., Allis C.D.;
RT "Serine 31 phosphorylation of histone variant H3.3 is specific to
RT regions bordering centromeres in metaphase chromosomes.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:6344-6349(2005).
RN [22]
RP FUNCTION.
RX PubMed=16258499; DOI=10.1038/sj.embor.7400561;
RA Daury L., Chailleux C., Bonvallet J., Trouche D.;
RT "Histone H3.3 deposition at E2F-regulated genes is linked to
RT transcription.";
RL EMBO Rep. 7:66-71(2006).
RN [23]
RP ACETYLATION AT LYS-10; LYS-15; LYS-19; LYS-24 AND LYS-28, METHYLATION
RP AT LYS-5; LYS-10; LYS-19; LYS-28; LYS-37; LYS-65; LYS-80 AND LYS-123,
RP AND MASS SPECTROMETRY.
RX PubMed=16267050; DOI=10.1074/jbc.M509266200;
RA Hake S.B., Garcia B.A., Duncan E.M., Kauer M., Dellaire G.,
RA Shabanowitz J., Bazett-Jones D.P., Allis C.D., Hunt D.F.;
RT "Expression patterns and post-translational modifications associated
RT with mammalian histone H3 variants.";
RL J. Biol. Chem. 281:559-568(2006).
RN [24]
RP METHYLATION AT LYS-5 AND LYS-10, ACETYLATION AT LYS-10, AND MASS
RP SPECTROMETRY.
RX PubMed=16457588; DOI=10.1021/pr050266a;
RA Thomas C.E., Kelleher N.L., Mizzen C.A.;
RT "Mass spectrometric characterization of human histone H3: a bird's eye
RT view.";
RL J. Proteome Res. 5:240-247(2006).
RN [25]
RP ACETYLATION AT LYS-10 AND LYS-15, METHYLATION AT ARG-18, AND
RP CITRULLINATION AT ARG-18.
RX PubMed=16497732; DOI=10.1210/me.2005-0365;
RA Miao F., Li S., Chavez V., Lanting L., Natarajan R.;
RT "Coactivator-associated arginine methyltransferase-1 enhances nuclear
RT factor-kappaB-mediated gene transcription through methylation of
RT histone H3 at arginine 17.";
RL Mol. Endocrinol. 20:1562-1573(2006).
RN [26]
RP METHYLATION AT ARG-3 BY PRMT6.
RX PubMed=18079182; DOI=10.1101/gad.447007;
RA Hyllus D., Stein C., Schnabel K., Schiltz E., Imhof A., Dou Y.,
RA Hsieh J., Bauer U.M.;
RT "PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4
RT trimethylation.";
RL Genes Dev. 21:3369-3380(2007).
RN [27]
RP ACETYLATION AT LYS-5; LYS-10; LYS-15; LYS-19; LYS-24; LYS-28; LYS-37;
RP LYS-57 AND LYS-80, METHYLATION AT LYS-5; LYS-10; LYS-19; LYS-24;
RP LYS-28; LYS-37; LYS-57; LYS-65; LYS-80 AND LYS-123, AND MASS
RP SPECTROMETRY.
RX PubMed=17194708; DOI=10.1074/jbc.M607900200;
RA Garcia B.A., Hake S.B., Diaz R.L., Kauer M., Morris S.A., Recht J.,
RA Shabanowitz J., Mishra N., Strahl B.D., Allis C.D., Hunt D.F.;
RT "Organismal differences in post-translational modifications in
RT histones H3 and H4.";
RL J. Biol. Chem. 282:7641-7655(2007).
RN [28]
RP ACETYLATION AT LYS-37.
RX PubMed=17189264; DOI=10.1074/jbc.M607909200;
RA Morris S.A., Rao B., Garcia B.A., Hake S.B., Diaz R.L.,
RA Shabanowitz J., Hunt D.F., Allis C.D., Lieb J.D., Strahl B.D.;
RT "Identification of histone H3 lysine 36 acetylation as a highly
RT conserved histone modification.";
RL J. Biol. Chem. 282:7632-7640(2007).
RN [29]
RP METHYLATION AT ARG-3 BY PRMT6.
RX PubMed=17898714; DOI=10.1038/nature06166;
RA Guccione E., Bassi C., Casadio F., Martinato F., Cesaroni M.,
RA Schuchlautz H., Luescher B., Amati B.;
RT "Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are
RT mutually exclusive.";
RL Nature 449:933-937(2007).
RN [30]
RP METHYLATION AT ARG-3 BY PRMT6.
RX PubMed=18077460; DOI=10.1074/jbc.C700192200;
RA Iberg A.N., Espejo A., Cheng D., Kim D., Michaud-Levesque J.,
RA Richard S., Bedford M.T.;
RT "Arginine methylation of the histone H3 tail impedes effector
RT binding.";
RL J. Biol. Chem. 283:3006-3010(2008).
RN [31]
RP PHOSPHORYLATION AT THR-12.
RX PubMed=18066052; DOI=10.1038/ncb1668;
RA Metzger E., Yin N., Wissmann M., Kunowska N., Fischer K.,
RA Friedrichs N., Patnaik D., Higgins J.M., Potier N., Scheidtmann K.H.,
RA Buettner R., Schule R.;
RT "Phosphorylation of histone H3 at threonine 11 establishes a novel
RT chromatin mark for transcriptional regulation.";
RL Nat. Cell Biol. 10:53-60(2008).
RN [32]
RP ACETYLATION AT LYS-116 AND LYS-123.
RX PubMed=19520870; DOI=10.1074/jbc.M109.003202;
RA Manohar M., Mooney A.M., North J.A., Nakkula R.J., Picking J.W.,
RA Edon A., Fishel R., Poirier M.G., Ottesen J.J.;
RT "Acetylation of histone H3 at the nucleosome dyad alters DNA-histone
RT binding.";
RL J. Biol. Chem. 284:23312-23321(2009).
RN [33]
RP PHOSPHORYLATION AT TYR-42.
RX PubMed=19783980; DOI=10.1038/nature08448;
RA Dawson M.A., Bannister A.J., Gottgens B., Foster S.D., Bartke T.,
RA Green A.R., Kouzarides T.;
RT "JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from
RT chromatin.";
RL Nature 461:819-822(2009).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [35]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-28 AND LYS-37, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [36]
RP PHOSPHORYLATION AT SER-58 AND THR-81.
RX PubMed=20850016; DOI=10.1016/j.cell.2010.08.020;
RA Vermeulen M., Eberl H.C., Matarese F., Marks H., Denissov S.,
RA Butter F., Lee K.K., Olsen J.V., Hyman A.A., Stunnenberg H.G.,
RA Mann M.;
RT "Quantitative interaction proteomics and genome-wide profiling of
RT epigenetic histone marks and their readers.";
RL Cell 142:967-980(2010).
RN [37]
RP PHOSPHORYLATION AT THR-7.
RX PubMed=20228790; DOI=10.1038/nature08839;
RA Metzger E., Imhof A., Patel D., Kahl P., Hoffmeyer K., Friedrichs N.,
RA Muller J.M., Greschik H., Kirfel J., Ji S., Kunowska N.,
RA Beisenherz-Huss C., Gunther T., Buettner R., Schule R.;
RT "Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation
RT at histone H3K4.";
RL Nature 464:792-796(2010).
RN [38]
RP CROTONYLATION AT LYS-5; LYS-10; LYS-19; LYS-24; LYS-28 AND LYS-57.
RX PubMed=21925322; DOI=10.1016/j.cell.2011.08.008;
RA Tan M., Luo H., Lee S., Jin F., Yang J.S., Montellier E., Buchou T.,
RA Cheng Z., Rousseaux S., Rajagopal N., Lu Z., Ye Z., Zhu Q.,
RA Wysocka J., Ye Y., Khochbin S., Ren B., Zhao Y.;
RT "Identification of 67 histone marks and histone lysine crotonylation
RT as a new type of histone modification.";
RL Cell 146:1016-1028(2011).
RN [39]
RP METHYLATION AT LYS-57.
RX PubMed=22387026; DOI=10.1016/j.molcel.2012.01.019;
RA Yu Y., Song C., Zhang Q., Dimaggio P.A., Garcia B.A., York A.,
RA Carey M.F., Grunstein M.;
RT "Histone H3 lysine 56 methylation regulates DNA replication through
RT its interaction with PCNA.";
RL Mol. Cell 46:7-17(2012).
RN [40]
RP ALLYSINE AT LYS-5.
RX PubMed=22483618; DOI=10.1016/j.molcel.2012.03.002;
RA Herranz N., Dave N., Millanes-Romero A., Morey L., Diaz V.M.,
RA Lorenz-Fonfria V., Gutierrez-Gallego R., Jeronimo C., Di Croce L.,
RA Garcia de Herreros A., Peiro S.;
RT "Lysyl oxidase-like 2 deaminates lysine 4 in histone H3.";
RL Mol. Cell 46:369-376(2012).
RN [41]
RP ACETYLATION AT LYS-123.
RX PubMed=23415232; DOI=10.1016/j.cell.2013.01.032;
RA Tropberger P., Pott S., Keller C., Kamieniarz-Gdula K., Caron M.,
RA Richter F., Li G., Mittler G., Liu E.T., Buhler M., Margueron R.,
RA Schneider R.;
RT "Regulation of transcription through acetylation of H3K122 on the
RT lateral surface of the histone octamer.";
RL Cell 152:859-872(2013).
CC -!- FUNCTION: Variant histone H3 which replaces conventional H3 in a
CC wide range of nucleosomes in active genes. Constitutes the
CC predominant form of histone H3 in non-dividing cells and is
CC incorporated into chromatin independently of DNA synthesis.
CC Deposited at sites of nucleosomal displacement throughout
CC transcribed genes, suggesting that it represents an epigenetic
CC imprint of transcriptionally active chromatin. Nucleosomes wrap
CC and compact DNA into chromatin, limiting DNA accessibility to the
CC cellular machineries which require DNA as a template. Histones
CC thereby play a central role in transcription regulation, DNA
CC repair, DNA replication and chromosomal stability. DNA
CC accessibility is regulated via a complex set of post-translational
CC modifications of histones, also called histone code, and
CC nucleosome remodeling.
CC -!- SUBUNIT: The nucleosome is a histone octamer containing two
CC molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4
CC heterotetramer and two H2A-H2B heterodimers. The octamer wraps
CC approximately 147 bp of DNA. Interacts with HIRA, a chaperone
CC required for its incorporation into nucleosomes.
CC -!- INTERACTION:
CC P45973:CBX5; NbExp=2; IntAct=EBI-120658, EBI-78219;
CC Q9Y6K1:DNMT3A; NbExp=7; IntAct=EBI-120658, EBI-923653;
CC Q8IZL8:PELP1; NbExp=11; IntAct=EBI-120658, EBI-716449;
CC Q9VK33:Sfmbt (xeno); NbExp=15; IntAct=EBI-120658, EBI-117801;
CC Q5VWG9:TAF3; NbExp=3; IntAct=EBI-120658, EBI-1560087;
CC -!- SUBCELLULAR LOCATION: Nucleus. Chromosome.
CC -!- DEVELOPMENTAL STAGE: Expressed throughout the cell cycle
CC independently of DNA synthesis.
CC -!- PTM: Acetylation is generally linked to gene activation.
CC Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9
CC (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac)
CC favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123
CC (H3K122ac) by EP300/p300 plays a central role in chromatin
CC structure: localizes at the surface of the histone octamer and
CC stimulates transcription, possibly by promoting nucleosome
CC instability.
CC -!- PTM: Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by
CC PADI4 impairs methylation and represses transcription.
CC -!- PTM: Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is
CC linked to gene activation. Symmetric dimethylation at Arg-9
CC (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric
CC dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene
CC repression and is mutually exclusive with H3 Lys-5 methylation
CC (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes
CC regardless of their transcription state and is enriched on
CC inactive promoters, while it is absent on active promoters.
CC -!- PTM: Specifically enriched in modifications associated with active
CC chromatin such as methylation at Lys-5 (H3K4me), Lys-37 and Lys-
CC 80. Methylation at Lys-5 (H3K4me) facilitates subsequent
CC acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is
CC associated with DNA double-strand break (DSB) responses and is a
CC specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and
CC Lys-28 (H3K27me), which are linked to gene repression, are
CC underrepresented. Methylation at Lys-10 (H3K9me) is a specific
CC target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents
CC subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of
CC H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me)
CC require preliminary monoubiquitination of H2B at 'Lys-120'.
CC Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched
CC in inactive X chromosome chromatin. Monomethylation at Lys-57
CC (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA
CC and is required for DNA replication.
CC -!- PTM: Phosphorylated at Thr-4 (H3T3ph) by GSG2/haspin during
CC prophase and dephosphorylated during anaphase. Phosphorylation at
CC Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation
CC and cell-cycle progression during mitosis and meiosis. In addition
CC phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is
CC important during interphase because it enables the transcription
CC of genes following external stimulation, like mitogens, stress,
CC growth factors or UV irradiation and result in the activation of
CC genes, such as c-fos and c-jun. Phosphorylation at Ser-11
CC (H3S10ph), which is linked to gene activation, prevents
CC methylation at Lys-10 (H3K9me) but facilitates acetylation of H3
CC and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the
CC dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from
CC heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an
CC essential regulatory mechanism for neoplastic cell transformation.
CC Phosphorylated at Ser-29 (H3S28ph) by MLTK isoform 1, RPS6KA5 or
CC AURKB during mitosis or upon ultraviolet B irradiation.
CC Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for
CC epigenetic transcriptional activation that prevents demethylation
CC of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically
CC phosphorylated at Thr-12 (H3T11ph) from prophase to early
CC anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph)
CC by PKN1 is a specific tag for epigenetic transcriptional
CC activation that promotes demethylation of Lys-10 (H3K9me) by
CC KDM4C/JMJD2C. Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes
CC exclusion of CBX5 (HP1 alpha) from chromatin. Phosphorylation on
CC Ser-32 (H3S31ph) is specific to regions bordering centromeres in
CC metaphase chromosomes.
CC -!- PTM: Ubiquitinated. Monoubiquitinated by RAG1 in lymphoid cells,
CC monoubiquitination is required for V(D)J recombination (By
CC similarity).
CC -!- PTM: Lysine deamination at Lys-5 (H3K4all) to form allysine is
CC mediated by LOXL2. Allysine formation by LOXL2 only takes place on
CC H3K4me3 and results in gene repression (PubMed:22483618).
CC -!- PTM: Crotonylation (Kcr) is specifically present in male germ
CC cells and marks testis-specific genes in post-meiotic cells,
CC including X-linked genes that escape sex chromosome inactivation
CC in haploid cells. Crotonylation marks active promoters and
CC enhancers and confers resistance to transcriptional repressors. It
CC is also associated with post-meiotically activated genes on
CC autosomes.
CC -!- SIMILARITY: Belongs to the histone H3 family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAH73371.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Histone H3 entry;
CC URL="http://en.wikipedia.org/wiki/Histone_H3";
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DR EMBL; M11354; AAA52653.1; -; mRNA.
DR EMBL; M11353; AAA52654.1; -; mRNA.
DR EMBL; Z48950; CAA88778.1; -; Genomic_DNA.
DR EMBL; X05855; CAA29288.1; ALT_SEQ; Genomic_DNA.
DR EMBL; X05856; CAA29288.1; JOINED; Genomic_DNA.
DR EMBL; X05857; CAA29288.1; JOINED; Genomic_DNA.
DR EMBL; AF218029; AAG17271.1; -; mRNA.
DR EMBL; BX537379; CAD97621.1; -; mRNA.
DR EMBL; AL512343; CAH73371.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AL512343; CAH73372.1; -; Genomic_DNA.
DR EMBL; BC001124; AAH01124.1; -; mRNA.
DR EMBL; BC006497; AAH06497.1; -; mRNA.
DR EMBL; BC012813; AAH12813.1; -; mRNA.
DR EMBL; BC017558; AAH17558.1; -; mRNA.
DR EMBL; BC029405; AAH29405.1; -; mRNA.
DR EMBL; BC038989; AAH38989.1; -; mRNA.
DR EMBL; BC066901; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC067757; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC081560; AAH81560.1; -; mRNA.
DR EMBL; BC081561; AAH81561.1; -; mRNA.
DR EMBL; BC095447; AAH95447.1; -; mRNA.
DR EMBL; BC108701; AAI08702.1; -; mRNA.
DR PIR; A27501; HSHU33.
DR RefSeq; NP_002098.1; NM_002107.4.
DR RefSeq; NP_005315.1; NM_005324.3.
DR UniGene; Hs.180877; -.
DR UniGene; Hs.533624; -.
DR UniGene; Hs.726012; -.
DR PDB; 2L43; NMR; -; A=2-14.
DR PDB; 3ASK; X-ray; 2.90 A; P/Q/R=2-14.
DR PDB; 3ASL; X-ray; 1.41 A; B=2-12.
DR PDB; 3AV2; X-ray; 2.80 A; A/E=1-136.
DR PDB; 3JVK; X-ray; 1.80 A; C=13-20.
DR PDB; 3MUK; X-ray; 1.75 A; D=22-29.
DR PDB; 3MUL; X-ray; 1.65 A; D=13-20.
DR PDB; 3QL9; X-ray; 0.93 A; C=2-16.
DR PDB; 3QLA; X-ray; 1.60 A; C/F=2-16.
DR PDB; 3QLC; X-ray; 2.50 A; C/D=2-16.
DR PDB; 4GNE; X-ray; 1.47 A; B=2-8.
DR PDB; 4GNF; X-ray; 1.55 A; C=2-16.
DR PDB; 4GNG; X-ray; 1.73 A; B/F=2-16.
DR PDB; 4GU0; X-ray; 3.10 A; E/F=2-27.
DR PDB; 4GUR; X-ray; 2.51 A; C=2-22.
DR PDB; 4GUS; X-ray; 2.23 A; C=2-22.
DR PDB; 4GY5; X-ray; 2.96 A; E/F=2-18.
DR PDB; 4H9N; X-ray; 1.95 A; A=2-136.
DR PDB; 4H9O; X-ray; 2.05 A; A=2-136.
DR PDB; 4H9P; X-ray; 2.20 A; A=2-136.
DR PDB; 4H9Q; X-ray; 1.95 A; A=2-136.
DR PDB; 4H9R; X-ray; 2.20 A; A=2-136.
DR PDB; 4H9S; X-ray; 2.60 A; A/B=2-136.
DR PDB; 4HGA; X-ray; 2.80 A; B=1-136.
DR PDB; 4L58; X-ray; 1.48 A; B=2-13.
DR PDBsum; 2L43; -.
DR PDBsum; 3ASK; -.
DR PDBsum; 3ASL; -.
DR PDBsum; 3AV2; -.
DR PDBsum; 3JVK; -.
DR PDBsum; 3MUK; -.
DR PDBsum; 3MUL; -.
DR PDBsum; 3QL9; -.
DR PDBsum; 3QLA; -.
DR PDBsum; 3QLC; -.
DR PDBsum; 4GNE; -.
DR PDBsum; 4GNF; -.
DR PDBsum; 4GNG; -.
DR PDBsum; 4GU0; -.
DR PDBsum; 4GUR; -.
DR PDBsum; 4GUS; -.
DR PDBsum; 4GY5; -.
DR PDBsum; 4H9N; -.
DR PDBsum; 4H9O; -.
DR PDBsum; 4H9P; -.
DR PDBsum; 4H9Q; -.
DR PDBsum; 4H9R; -.
DR PDBsum; 4H9S; -.
DR PDBsum; 4HGA; -.
DR PDBsum; 4L58; -.
DR ProteinModelPortal; P84243; -.
DR SMR; P84243; 17-136.
DR DIP; DIP-40046N; -.
DR IntAct; P84243; 30.
DR MINT; MINT-4825076; -.
DR STRING; 9606.ENSP00000254810; -.
DR PhosphoSite; P84243; -.
DR PaxDb; P84243; -.
DR PRIDE; P84243; -.
DR DNASU; 3020; -.
DR DNASU; 3021; -.
DR Ensembl; ENST00000254810; ENSP00000254810; ENSG00000132475.
DR Ensembl; ENST00000366813; ENSP00000355778; ENSG00000163041.
DR Ensembl; ENST00000366815; ENSP00000355780; ENSG00000163041.
DR Ensembl; ENST00000366816; ENSP00000355781; ENSG00000163041.
DR Ensembl; ENST00000586607; ENSP00000466020; ENSG00000132475.
DR Ensembl; ENST00000587560; ENSP00000468714; ENSG00000132475.
DR Ensembl; ENST00000589599; ENSP00000465813; ENSG00000132475.
DR GeneID; 3020; -.
DR GeneID; 3021; -.
DR KEGG; hsa:3020; -.
DR KEGG; hsa:3021; -.
DR UCSC; uc001hpw.3; human.
DR CTD; 3020; -.
DR CTD; 3021; -.
DR H-InvDB; HIX0135637; -.
DR HGNC; HGNC:4764; H3F3A.
DR HGNC; HGNC:4765; H3F3B.
DR HPA; CAB011481; -.
DR HPA; CAB037221; -.
DR HPA; HPA042570; -.
DR MIM; 601058; gene.
DR MIM; 601128; gene.
DR neXtProt; NX_P84243; -.
DR PharmGKB; PA29140; -.
DR eggNOG; COG2036; -.
DR HOVERGEN; HBG001172; -.
DR InParanoid; P84243; -.
DR KO; K11253; -.
DR OMA; QEATESY; -.
DR Reactome; REACT_111183; Meiosis.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_604; Hemostasis.
DR EvolutionaryTrace; P84243; -.
DR GeneWiki; H3F3A; -.
DR NextBio; 11966; -.
DR PRO; PR:P84243; -.
DR ArrayExpress; P84243; -.
DR Bgee; P84243; -.
DR CleanEx; HS_H3F3A; -.
DR CleanEx; HS_H3F3B; -.
DR Genevestigator; P84243; -.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0000786; C:nucleosome; IEA:UniProtKB-KW.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0007420; P:brain development; IEA:Ensembl.
DR GO; GO:0006334; P:nucleosome assembly; IEA:InterPro.
DR GO; GO:0009725; P:response to hormone stimulus; IEA:Ensembl.
DR Gene3D; 1.10.20.10; -; 1.
DR InterPro; IPR009072; Histone-fold.
DR InterPro; IPR007125; Histone_core_D.
DR InterPro; IPR000164; Histone_H3.
DR PANTHER; PTHR11426; PTHR11426; 1.
DR Pfam; PF00125; Histone; 1.
DR PRINTS; PR00622; HISTONEH3.
DR SMART; SM00428; H3; 1.
DR SUPFAM; SSF47113; SSF47113; 1.
DR PROSITE; PS00322; HISTONE_H3_1; 1.
DR PROSITE; PS00959; HISTONE_H3_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Chromosome; Citrullination;
KW Complete proteome; Direct protein sequencing; DNA-binding;
KW Methylation; Nucleosome core; Nucleus; Phosphoprotein;
KW Reference proteome; Ubl conjugation.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 136 Histone H3.3.
FT /FTId=PRO_0000221247.
FT MOD_RES 3 3 Asymmetric dimethylarginine; by PRMT6.
FT MOD_RES 4 4 Phosphothreonine; by GSG2.
FT MOD_RES 5 5 Allysine; alternate.
FT MOD_RES 5 5 N6,N6,N6-trimethyllysine; alternate.
FT MOD_RES 5 5 N6,N6-dimethyllysine; alternate.
FT MOD_RES 5 5 N6-acetyllysine; alternate.
FT MOD_RES 5 5 N6-crotonyl-L-lysine; alternate.
FT MOD_RES 5 5 N6-methyllysine; alternate.
FT MOD_RES 7 7 Phosphothreonine; by PKC.
FT MOD_RES 9 9 Citrulline; alternate.
FT MOD_RES 9 9 Symmetric dimethylarginine; by PRMT5;
FT alternate (By similarity).
FT MOD_RES 10 10 N6,N6,N6-trimethyllysine; alternate.
FT MOD_RES 10 10 N6,N6-dimethyllysine; alternate.
FT MOD_RES 10 10 N6-acetyllysine; alternate.
FT MOD_RES 10 10 N6-crotonyl-L-lysine; alternate.
FT MOD_RES 10 10 N6-methyllysine; alternate.
FT MOD_RES 11 11 Phosphoserine; by AURKB, AURKC, RPS6KA3,
FT RPS6KA4 and RPS6KA5.
FT MOD_RES 12 12 Phosphothreonine; by PKC.
FT MOD_RES 15 15 N6-acetyllysine.
FT MOD_RES 18 18 Asymmetric dimethylarginine; by CARM1;
FT alternate.
FT MOD_RES 18 18 Citrulline; alternate.
FT MOD_RES 19 19 N6-acetyllysine; alternate.
FT MOD_RES 19 19 N6-crotonyl-L-lysine; alternate.
FT MOD_RES 19 19 N6-methyllysine; alternate.
FT MOD_RES 24 24 N6-acetyllysine; alternate.
FT MOD_RES 24 24 N6-crotonyl-L-lysine; alternate.
FT MOD_RES 24 24 N6-methyllysine; alternate.
FT MOD_RES 28 28 N6,N6,N6-trimethyllysine; alternate.
FT MOD_RES 28 28 N6,N6-dimethyllysine; alternate.
FT MOD_RES 28 28 N6-acetyllysine; alternate.
FT MOD_RES 28 28 N6-crotonyl-L-lysine; alternate.
FT MOD_RES 28 28 N6-methyllysine; alternate.
FT MOD_RES 29 29 Phosphoserine; by AURKB, AURKC and
FT RPS6KA5.
FT MOD_RES 32 32 Phosphoserine.
FT MOD_RES 37 37 N6,N6,N6-trimethyllysine; alternate.
FT MOD_RES 37 37 N6,N6-dimethyllysine; alternate.
FT MOD_RES 37 37 N6-acetyllysine; alternate.
FT MOD_RES 37 37 N6-methyllysine; alternate.
FT MOD_RES 38 38 N6-methyllysine (By similarity).
FT MOD_RES 42 42 Phosphotyrosine.
FT MOD_RES 57 57 N6,N6,N6-trimethyllysine; alternate.
FT MOD_RES 57 57 N6-acetyllysine; alternate.
FT MOD_RES 57 57 N6-crotonyl-L-lysine; alternate.
FT MOD_RES 57 57 N6-methyllysine; by EHMT2; alternate.
FT MOD_RES 58 58 Phosphoserine.
FT MOD_RES 65 65 N6-methyllysine.
FT MOD_RES 80 80 N6,N6,N6-trimethyllysine; alternate (By
FT similarity).
FT MOD_RES 80 80 N6,N6-dimethyllysine; alternate.
FT MOD_RES 80 80 N6-acetyllysine; alternate.
FT MOD_RES 80 80 N6-methyllysine; alternate.
FT MOD_RES 81 81 Phosphothreonine.
FT MOD_RES 108 108 Phosphothreonine (By similarity).
FT MOD_RES 116 116 N6-acetyllysine.
FT MOD_RES 123 123 N6-acetyllysine; alternate.
FT MOD_RES 123 123 N6-methyllysine; alternate.
FT CONFLICT 9 9 R -> L (in Ref. 7; AAH81561).
FT STRAND 4 6
FT HELIX 8 10
FT STRAND 45 47
FT HELIX 49 59
FT HELIX 65 79
FT STRAND 80 82
FT STRAND 84 86
FT HELIX 87 110
FT STRAND 118 120
FT HELIX 122 132
SQ SEQUENCE 136 AA; 15328 MW; 5158ED279E6F9E1C CRC64;
MARTKQTARK STGGKAPRKQ LATKAARKSA PSTGGVKKPH RYRPGTVALR EIRRYQKSTE
LLIRKLPFQR LVREIAQDFK TDLRFQSAAI GALQEASEAY LVGLFEDTNL CAIHAKRVTI
MPKDIQLARR IRGERA
//
ID H33_HUMAN Reviewed; 136 AA.
AC P84243; P06351; P33155; Q5VV55; Q5VV56; Q66I33; Q9V3W4;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 107.
DE RecName: Full=Histone H3.3;
GN Name=H3F3A; Synonyms=H3.3A, H3F3; ORFNames=PP781;
GN and
GN Name=H3F3B; Synonyms=H3.3B;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (H3F3A).
RC TISSUE=Fibroblast;
RX PubMed=2859593; DOI=10.1073/pnas.82.9.2834;
RA Wells D., Kedes L.;
RT "Structure of a human histone cDNA: evidence that basally expressed
RT histone genes have intervening sequences and encode polyadenylylated
RT mRNAs.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:2834-2838(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (H3F3A).
RX PubMed=3031613; DOI=10.1093/nar/15.7.2871;
RA Wells D., Hoffman D., Kedes L.;
RT "Unusual structure, evolutionary conservation of non-coding sequences
RT and numerous pseudogenes characterize the human H3.3 histone multigene
RT family.";
RL Nucleic Acids Res. 15:2871-2889(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (H3F3B).
RC TISSUE=Testis;
RX PubMed=8586426; DOI=10.1006/geno.1995.9878;
RA Albig W., Bramlage B., Gruber K., Klobeck H.-G., Kunz J., Doenecke D.;
RT "The human replacement histone H3.3B gene (H3F3B).";
RL Genomics 30:264-272(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15498874; DOI=10.1073/pnas.0404089101;
RA Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H.,
RA Qiu X., Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y.,
RA Shu H., Chen X., Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S.,
RA Gu J.;
RT "Large-scale cDNA transfection screening for genes related to cancer
RT development and progression.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (H3F3B).
RC TISSUE=Retina;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (H3F3A AND H3F3B).
RC TISSUE=Bone marrow, Brain, Colon, Eye, Lung, Muscle, Spinal cord,
RC Testis, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP PARTIAL PROTEIN SEQUENCE, METHYLATION AT LYS-10; LYS-28 AND LYS-37,
RP AND ACETYLATION AT LYS-15 AND LYS-24.
RX PubMed=7309716;
RA Ohe Y., Iwai K.;
RT "Human spleen histone H3. Isolation and amino acid sequence.";
RL J. Biochem. 90:1205-1211(1981).
RN [9]
RP PROTEIN SEQUENCE OF 28-41, METHYLATION AT LYS-5; LYS-10; LYS-28 AND
RP LYS-37, PHOSPHORYLATION AT THR-4; SER-11; SER-29 AND SER-32,
RP ACETYLATION AT LYS-10 AND LYS-15, AND MASS SPECTROMETRY.
RX PubMed=16185088; DOI=10.1021/bi050906n;
RA Garcia B.A., Barber C.M., Hake S.B., Ptak C., Turner F.B., Busby S.A.,
RA Shabanowitz J., Moran R.G., Allis C.D., Hunt D.F.;
RT "Modifications of human histone H3 variants during mitosis.";
RL Biochemistry 44:13202-13213(2005).
RN [10]
RP PROTEIN SEQUENCE OF 58-64; 117-120 AND 124-135, AND PHOSPHORYLATION AT
RP SER-11 AND SER-29.
RX PubMed=10464286; DOI=10.1074/jbc.274.36.25543;
RA Goto H., Tomono Y., Ajiro K., Kosako H., Fujita M., Sakurai M.,
RA Okawa K., Iwamatsu A., Okigaki T., Takahashi T., Inagaki M.;
RT "Identification of a novel phosphorylation site on histone H3 coupled
RT with mitotic chromosome condensation.";
RL J. Biol. Chem. 274:25543-25549(1999).
RN [11]
RP METHYLATION AT LYS-10.
RX PubMed=11242053; DOI=10.1038/35065132;
RA Lachner M., O'Carroll D., Rea S., Mechtler K., Jenuwein T.;
RT "Methylation of histone H3 lysine 9 creates a binding site for HP1
RT proteins.";
RL Nature 410:116-120(2001).
RN [12]
RP PHOSPHORYLATION AT SER-11 AND SER-29.
RX PubMed=11856369; DOI=10.1046/j.1356-9597.2001.00498.x;
RA Goto H., Yasui Y., Nigg E.A., Inagaki M.;
RT "Aurora-B phosphorylates Histone H3 at serine28 with regard to the
RT mitotic chromosome condensation.";
RL Genes Cells 7:11-17(2002).
RN [13]
RP PHOSPHORYLATION AT SER-11 AND THR-12.
RX PubMed=12560483; DOI=10.1093/nar/gkg176;
RA Preuss U., Landsberg G., Scheidtmann K.H.;
RT "Novel mitosis-specific phosphorylation of histone H3 at Thr11
RT mediated by Dlk/ZIP kinase.";
RL Nucleic Acids Res. 31:878-885(2003).
RN [14]
RP FUNCTION, AND INTERACTION WITH HIRA.
RX PubMed=14718166; DOI=10.1016/S0092-8674(03)01064-X;
RA Tagami H., Ray-Gallet D., Almouzni G., Nakatani Y.;
RT "Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways
RT dependent or independent of DNA synthesis.";
RL Cell 116:51-61(2004).
RN [15]
RP METHYLATION AT ARG-18.
RX PubMed=15471871; DOI=10.1074/jbc.M410021200;
RA Ananthanarayanan M., Li S., Balasubramaniyan N., Suchy F.J.,
RA Walsh M.J.;
RT "Ligand-dependent activation of the farnesoid X-receptor directs
RT arginine methylation of histone H3 by CARM1.";
RL J. Biol. Chem. 279:54348-54357(2004).
RN [16]
RP METHYLATION AT LYS-80.
RX PubMed=15525939; DOI=10.1038/nature03114;
RA Huyen Y., Zgheib O., Ditullio R.A. Jr., Gorgoulis V.G., Zacharatos P.,
RA Petty T.J., Sheston E.A., Mellert H.S., Stavridi E.S.,
RA Halazonetis T.D.;
RT "Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand
RT breaks.";
RL Nature 432:406-411(2004).
RN [17]
RP CITRULLINATION AT ARG-9 AND ARG-18, AND METHYLATION AT ARG-18.
RX PubMed=15345777; DOI=10.1126/science.1101400;
RA Wang Y., Wysocka J., Sayegh J., Lee Y.-H., Perlin J.R., Leonelli L.,
RA Sonbuchner L.S., McDonald C.H., Cook R.G., Dou Y., Roeder R.G.,
RA Clarke S., Stallcup M.R., Allis C.D., Coonrod S.A.;
RT "Human PAD4 regulates histone arginine methylation levels via
RT demethylimination.";
RL Science 306:279-283(2004).
RN [18]
RP FUNCTION.
RX PubMed=15776021; DOI=10.1038/sj.embor.7400366;
RA Chow C.-M., Georgiou A., Szutorisz H., Maia e Silva A., Pombo A.,
RA Barahona I., Dargelos E., Canzonetta C., Dillon N.;
RT "Variant histone H3.3 marks promoters of transcriptionally active
RT genes during mammalian cell division.";
RL EMBO Rep. 6:354-360(2005).
RN [19]
RP PHOSPHORYLATION AT THR-4; SER-11 AND SER-29.
RX PubMed=15681610; DOI=10.1101/gad.1267105;
RA Dai J., Sultan S., Taylor S.S., Higgins J.M.G.;
RT "The kinase haspin is required for mitotic histone H3 Thr 3
RT phosphorylation and normal metaphase chromosome alignment.";
RL Genes Dev. 19:472-488(2005).
RN [20]
RP PHOSPHORYLATION AT SER-29.
RX PubMed=15684425; DOI=10.1074/jbc.M410521200;
RA Choi H.S., Choi B.Y., Cho Y.-Y., Zhu F., Bode A.M., Dong Z.;
RT "Phosphorylation of Ser28 in histone H3 mediated by mixed lineage
RT kinase-like mitogen-activated protein triple kinase alpha.";
RL J. Biol. Chem. 280:13545-13553(2005).
RN [21]
RP PHOSPHORYLATION AT SER-11; SER-29 AND SER-32, AND MASS SPECTROMETRY.
RX PubMed=15851689; DOI=10.1073/pnas.0502413102;
RA Hake S.B., Garcia B.A., Kauer M., Baker S.P., Shabanowitz J.,
RA Hunt D.F., Allis C.D.;
RT "Serine 31 phosphorylation of histone variant H3.3 is specific to
RT regions bordering centromeres in metaphase chromosomes.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:6344-6349(2005).
RN [22]
RP FUNCTION.
RX PubMed=16258499; DOI=10.1038/sj.embor.7400561;
RA Daury L., Chailleux C., Bonvallet J., Trouche D.;
RT "Histone H3.3 deposition at E2F-regulated genes is linked to
RT transcription.";
RL EMBO Rep. 7:66-71(2006).
RN [23]
RP ACETYLATION AT LYS-10; LYS-15; LYS-19; LYS-24 AND LYS-28, METHYLATION
RP AT LYS-5; LYS-10; LYS-19; LYS-28; LYS-37; LYS-65; LYS-80 AND LYS-123,
RP AND MASS SPECTROMETRY.
RX PubMed=16267050; DOI=10.1074/jbc.M509266200;
RA Hake S.B., Garcia B.A., Duncan E.M., Kauer M., Dellaire G.,
RA Shabanowitz J., Bazett-Jones D.P., Allis C.D., Hunt D.F.;
RT "Expression patterns and post-translational modifications associated
RT with mammalian histone H3 variants.";
RL J. Biol. Chem. 281:559-568(2006).
RN [24]
RP METHYLATION AT LYS-5 AND LYS-10, ACETYLATION AT LYS-10, AND MASS
RP SPECTROMETRY.
RX PubMed=16457588; DOI=10.1021/pr050266a;
RA Thomas C.E., Kelleher N.L., Mizzen C.A.;
RT "Mass spectrometric characterization of human histone H3: a bird's eye
RT view.";
RL J. Proteome Res. 5:240-247(2006).
RN [25]
RP ACETYLATION AT LYS-10 AND LYS-15, METHYLATION AT ARG-18, AND
RP CITRULLINATION AT ARG-18.
RX PubMed=16497732; DOI=10.1210/me.2005-0365;
RA Miao F., Li S., Chavez V., Lanting L., Natarajan R.;
RT "Coactivator-associated arginine methyltransferase-1 enhances nuclear
RT factor-kappaB-mediated gene transcription through methylation of
RT histone H3 at arginine 17.";
RL Mol. Endocrinol. 20:1562-1573(2006).
RN [26]
RP METHYLATION AT ARG-3 BY PRMT6.
RX PubMed=18079182; DOI=10.1101/gad.447007;
RA Hyllus D., Stein C., Schnabel K., Schiltz E., Imhof A., Dou Y.,
RA Hsieh J., Bauer U.M.;
RT "PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4
RT trimethylation.";
RL Genes Dev. 21:3369-3380(2007).
RN [27]
RP ACETYLATION AT LYS-5; LYS-10; LYS-15; LYS-19; LYS-24; LYS-28; LYS-37;
RP LYS-57 AND LYS-80, METHYLATION AT LYS-5; LYS-10; LYS-19; LYS-24;
RP LYS-28; LYS-37; LYS-57; LYS-65; LYS-80 AND LYS-123, AND MASS
RP SPECTROMETRY.
RX PubMed=17194708; DOI=10.1074/jbc.M607900200;
RA Garcia B.A., Hake S.B., Diaz R.L., Kauer M., Morris S.A., Recht J.,
RA Shabanowitz J., Mishra N., Strahl B.D., Allis C.D., Hunt D.F.;
RT "Organismal differences in post-translational modifications in
RT histones H3 and H4.";
RL J. Biol. Chem. 282:7641-7655(2007).
RN [28]
RP ACETYLATION AT LYS-37.
RX PubMed=17189264; DOI=10.1074/jbc.M607909200;
RA Morris S.A., Rao B., Garcia B.A., Hake S.B., Diaz R.L.,
RA Shabanowitz J., Hunt D.F., Allis C.D., Lieb J.D., Strahl B.D.;
RT "Identification of histone H3 lysine 36 acetylation as a highly
RT conserved histone modification.";
RL J. Biol. Chem. 282:7632-7640(2007).
RN [29]
RP METHYLATION AT ARG-3 BY PRMT6.
RX PubMed=17898714; DOI=10.1038/nature06166;
RA Guccione E., Bassi C., Casadio F., Martinato F., Cesaroni M.,
RA Schuchlautz H., Luescher B., Amati B.;
RT "Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are
RT mutually exclusive.";
RL Nature 449:933-937(2007).
RN [30]
RP METHYLATION AT ARG-3 BY PRMT6.
RX PubMed=18077460; DOI=10.1074/jbc.C700192200;
RA Iberg A.N., Espejo A., Cheng D., Kim D., Michaud-Levesque J.,
RA Richard S., Bedford M.T.;
RT "Arginine methylation of the histone H3 tail impedes effector
RT binding.";
RL J. Biol. Chem. 283:3006-3010(2008).
RN [31]
RP PHOSPHORYLATION AT THR-12.
RX PubMed=18066052; DOI=10.1038/ncb1668;
RA Metzger E., Yin N., Wissmann M., Kunowska N., Fischer K.,
RA Friedrichs N., Patnaik D., Higgins J.M., Potier N., Scheidtmann K.H.,
RA Buettner R., Schule R.;
RT "Phosphorylation of histone H3 at threonine 11 establishes a novel
RT chromatin mark for transcriptional regulation.";
RL Nat. Cell Biol. 10:53-60(2008).
RN [32]
RP ACETYLATION AT LYS-116 AND LYS-123.
RX PubMed=19520870; DOI=10.1074/jbc.M109.003202;
RA Manohar M., Mooney A.M., North J.A., Nakkula R.J., Picking J.W.,
RA Edon A., Fishel R., Poirier M.G., Ottesen J.J.;
RT "Acetylation of histone H3 at the nucleosome dyad alters DNA-histone
RT binding.";
RL J. Biol. Chem. 284:23312-23321(2009).
RN [33]
RP PHOSPHORYLATION AT TYR-42.
RX PubMed=19783980; DOI=10.1038/nature08448;
RA Dawson M.A., Bannister A.J., Gottgens B., Foster S.D., Bartke T.,
RA Green A.R., Kouzarides T.;
RT "JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from
RT chromatin.";
RL Nature 461:819-822(2009).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [35]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-28 AND LYS-37, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [36]
RP PHOSPHORYLATION AT SER-58 AND THR-81.
RX PubMed=20850016; DOI=10.1016/j.cell.2010.08.020;
RA Vermeulen M., Eberl H.C., Matarese F., Marks H., Denissov S.,
RA Butter F., Lee K.K., Olsen J.V., Hyman A.A., Stunnenberg H.G.,
RA Mann M.;
RT "Quantitative interaction proteomics and genome-wide profiling of
RT epigenetic histone marks and their readers.";
RL Cell 142:967-980(2010).
RN [37]
RP PHOSPHORYLATION AT THR-7.
RX PubMed=20228790; DOI=10.1038/nature08839;
RA Metzger E., Imhof A., Patel D., Kahl P., Hoffmeyer K., Friedrichs N.,
RA Muller J.M., Greschik H., Kirfel J., Ji S., Kunowska N.,
RA Beisenherz-Huss C., Gunther T., Buettner R., Schule R.;
RT "Phosphorylation of histone H3T6 by PKCbeta(I) controls demethylation
RT at histone H3K4.";
RL Nature 464:792-796(2010).
RN [38]
RP CROTONYLATION AT LYS-5; LYS-10; LYS-19; LYS-24; LYS-28 AND LYS-57.
RX PubMed=21925322; DOI=10.1016/j.cell.2011.08.008;
RA Tan M., Luo H., Lee S., Jin F., Yang J.S., Montellier E., Buchou T.,
RA Cheng Z., Rousseaux S., Rajagopal N., Lu Z., Ye Z., Zhu Q.,
RA Wysocka J., Ye Y., Khochbin S., Ren B., Zhao Y.;
RT "Identification of 67 histone marks and histone lysine crotonylation
RT as a new type of histone modification.";
RL Cell 146:1016-1028(2011).
RN [39]
RP METHYLATION AT LYS-57.
RX PubMed=22387026; DOI=10.1016/j.molcel.2012.01.019;
RA Yu Y., Song C., Zhang Q., Dimaggio P.A., Garcia B.A., York A.,
RA Carey M.F., Grunstein M.;
RT "Histone H3 lysine 56 methylation regulates DNA replication through
RT its interaction with PCNA.";
RL Mol. Cell 46:7-17(2012).
RN [40]
RP ALLYSINE AT LYS-5.
RX PubMed=22483618; DOI=10.1016/j.molcel.2012.03.002;
RA Herranz N., Dave N., Millanes-Romero A., Morey L., Diaz V.M.,
RA Lorenz-Fonfria V., Gutierrez-Gallego R., Jeronimo C., Di Croce L.,
RA Garcia de Herreros A., Peiro S.;
RT "Lysyl oxidase-like 2 deaminates lysine 4 in histone H3.";
RL Mol. Cell 46:369-376(2012).
RN [41]
RP ACETYLATION AT LYS-123.
RX PubMed=23415232; DOI=10.1016/j.cell.2013.01.032;
RA Tropberger P., Pott S., Keller C., Kamieniarz-Gdula K., Caron M.,
RA Richter F., Li G., Mittler G., Liu E.T., Buhler M., Margueron R.,
RA Schneider R.;
RT "Regulation of transcription through acetylation of H3K122 on the
RT lateral surface of the histone octamer.";
RL Cell 152:859-872(2013).
CC -!- FUNCTION: Variant histone H3 which replaces conventional H3 in a
CC wide range of nucleosomes in active genes. Constitutes the
CC predominant form of histone H3 in non-dividing cells and is
CC incorporated into chromatin independently of DNA synthesis.
CC Deposited at sites of nucleosomal displacement throughout
CC transcribed genes, suggesting that it represents an epigenetic
CC imprint of transcriptionally active chromatin. Nucleosomes wrap
CC and compact DNA into chromatin, limiting DNA accessibility to the
CC cellular machineries which require DNA as a template. Histones
CC thereby play a central role in transcription regulation, DNA
CC repair, DNA replication and chromosomal stability. DNA
CC accessibility is regulated via a complex set of post-translational
CC modifications of histones, also called histone code, and
CC nucleosome remodeling.
CC -!- SUBUNIT: The nucleosome is a histone octamer containing two
CC molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4
CC heterotetramer and two H2A-H2B heterodimers. The octamer wraps
CC approximately 147 bp of DNA. Interacts with HIRA, a chaperone
CC required for its incorporation into nucleosomes.
CC -!- INTERACTION:
CC P45973:CBX5; NbExp=2; IntAct=EBI-120658, EBI-78219;
CC Q9Y6K1:DNMT3A; NbExp=7; IntAct=EBI-120658, EBI-923653;
CC Q8IZL8:PELP1; NbExp=11; IntAct=EBI-120658, EBI-716449;
CC Q9VK33:Sfmbt (xeno); NbExp=15; IntAct=EBI-120658, EBI-117801;
CC Q5VWG9:TAF3; NbExp=3; IntAct=EBI-120658, EBI-1560087;
CC -!- SUBCELLULAR LOCATION: Nucleus. Chromosome.
CC -!- DEVELOPMENTAL STAGE: Expressed throughout the cell cycle
CC independently of DNA synthesis.
CC -!- PTM: Acetylation is generally linked to gene activation.
CC Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9
CC (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac)
CC favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123
CC (H3K122ac) by EP300/p300 plays a central role in chromatin
CC structure: localizes at the surface of the histone octamer and
CC stimulates transcription, possibly by promoting nucleosome
CC instability.
CC -!- PTM: Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by
CC PADI4 impairs methylation and represses transcription.
CC -!- PTM: Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is
CC linked to gene activation. Symmetric dimethylation at Arg-9
CC (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric
CC dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene
CC repression and is mutually exclusive with H3 Lys-5 methylation
CC (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes
CC regardless of their transcription state and is enriched on
CC inactive promoters, while it is absent on active promoters.
CC -!- PTM: Specifically enriched in modifications associated with active
CC chromatin such as methylation at Lys-5 (H3K4me), Lys-37 and Lys-
CC 80. Methylation at Lys-5 (H3K4me) facilitates subsequent
CC acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is
CC associated with DNA double-strand break (DSB) responses and is a
CC specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and
CC Lys-28 (H3K27me), which are linked to gene repression, are
CC underrepresented. Methylation at Lys-10 (H3K9me) is a specific
CC target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents
CC subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of
CC H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me)
CC require preliminary monoubiquitination of H2B at 'Lys-120'.
CC Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched
CC in inactive X chromosome chromatin. Monomethylation at Lys-57
CC (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA
CC and is required for DNA replication.
CC -!- PTM: Phosphorylated at Thr-4 (H3T3ph) by GSG2/haspin during
CC prophase and dephosphorylated during anaphase. Phosphorylation at
CC Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation
CC and cell-cycle progression during mitosis and meiosis. In addition
CC phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is
CC important during interphase because it enables the transcription
CC of genes following external stimulation, like mitogens, stress,
CC growth factors or UV irradiation and result in the activation of
CC genes, such as c-fos and c-jun. Phosphorylation at Ser-11
CC (H3S10ph), which is linked to gene activation, prevents
CC methylation at Lys-10 (H3K9me) but facilitates acetylation of H3
CC and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the
CC dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from
CC heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an
CC essential regulatory mechanism for neoplastic cell transformation.
CC Phosphorylated at Ser-29 (H3S28ph) by MLTK isoform 1, RPS6KA5 or
CC AURKB during mitosis or upon ultraviolet B irradiation.
CC Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for
CC epigenetic transcriptional activation that prevents demethylation
CC of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically
CC phosphorylated at Thr-12 (H3T11ph) from prophase to early
CC anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph)
CC by PKN1 is a specific tag for epigenetic transcriptional
CC activation that promotes demethylation of Lys-10 (H3K9me) by
CC KDM4C/JMJD2C. Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes
CC exclusion of CBX5 (HP1 alpha) from chromatin. Phosphorylation on
CC Ser-32 (H3S31ph) is specific to regions bordering centromeres in
CC metaphase chromosomes.
CC -!- PTM: Ubiquitinated. Monoubiquitinated by RAG1 in lymphoid cells,
CC monoubiquitination is required for V(D)J recombination (By
CC similarity).
CC -!- PTM: Lysine deamination at Lys-5 (H3K4all) to form allysine is
CC mediated by LOXL2. Allysine formation by LOXL2 only takes place on
CC H3K4me3 and results in gene repression (PubMed:22483618).
CC -!- PTM: Crotonylation (Kcr) is specifically present in male germ
CC cells and marks testis-specific genes in post-meiotic cells,
CC including X-linked genes that escape sex chromosome inactivation
CC in haploid cells. Crotonylation marks active promoters and
CC enhancers and confers resistance to transcriptional repressors. It
CC is also associated with post-meiotically activated genes on
CC autosomes.
CC -!- SIMILARITY: Belongs to the histone H3 family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAH73371.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Histone H3 entry;
CC URL="http://en.wikipedia.org/wiki/Histone_H3";
CC -----------------------------------------------------------------------
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DR EMBL; M11354; AAA52653.1; -; mRNA.
DR EMBL; M11353; AAA52654.1; -; mRNA.
DR EMBL; Z48950; CAA88778.1; -; Genomic_DNA.
DR EMBL; X05855; CAA29288.1; ALT_SEQ; Genomic_DNA.
DR EMBL; X05856; CAA29288.1; JOINED; Genomic_DNA.
DR EMBL; X05857; CAA29288.1; JOINED; Genomic_DNA.
DR EMBL; AF218029; AAG17271.1; -; mRNA.
DR EMBL; BX537379; CAD97621.1; -; mRNA.
DR EMBL; AL512343; CAH73371.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AL512343; CAH73372.1; -; Genomic_DNA.
DR EMBL; BC001124; AAH01124.1; -; mRNA.
DR EMBL; BC006497; AAH06497.1; -; mRNA.
DR EMBL; BC012813; AAH12813.1; -; mRNA.
DR EMBL; BC017558; AAH17558.1; -; mRNA.
DR EMBL; BC029405; AAH29405.1; -; mRNA.
DR EMBL; BC038989; AAH38989.1; -; mRNA.
DR EMBL; BC066901; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC067757; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC081560; AAH81560.1; -; mRNA.
DR EMBL; BC081561; AAH81561.1; -; mRNA.
DR EMBL; BC095447; AAH95447.1; -; mRNA.
DR EMBL; BC108701; AAI08702.1; -; mRNA.
DR PIR; A27501; HSHU33.
DR RefSeq; NP_002098.1; NM_002107.4.
DR RefSeq; NP_005315.1; NM_005324.3.
DR UniGene; Hs.180877; -.
DR UniGene; Hs.533624; -.
DR UniGene; Hs.726012; -.
DR PDB; 2L43; NMR; -; A=2-14.
DR PDB; 3ASK; X-ray; 2.90 A; P/Q/R=2-14.
DR PDB; 3ASL; X-ray; 1.41 A; B=2-12.
DR PDB; 3AV2; X-ray; 2.80 A; A/E=1-136.
DR PDB; 3JVK; X-ray; 1.80 A; C=13-20.
DR PDB; 3MUK; X-ray; 1.75 A; D=22-29.
DR PDB; 3MUL; X-ray; 1.65 A; D=13-20.
DR PDB; 3QL9; X-ray; 0.93 A; C=2-16.
DR PDB; 3QLA; X-ray; 1.60 A; C/F=2-16.
DR PDB; 3QLC; X-ray; 2.50 A; C/D=2-16.
DR PDB; 4GNE; X-ray; 1.47 A; B=2-8.
DR PDB; 4GNF; X-ray; 1.55 A; C=2-16.
DR PDB; 4GNG; X-ray; 1.73 A; B/F=2-16.
DR PDB; 4GU0; X-ray; 3.10 A; E/F=2-27.
DR PDB; 4GUR; X-ray; 2.51 A; C=2-22.
DR PDB; 4GUS; X-ray; 2.23 A; C=2-22.
DR PDB; 4GY5; X-ray; 2.96 A; E/F=2-18.
DR PDB; 4H9N; X-ray; 1.95 A; A=2-136.
DR PDB; 4H9O; X-ray; 2.05 A; A=2-136.
DR PDB; 4H9P; X-ray; 2.20 A; A=2-136.
DR PDB; 4H9Q; X-ray; 1.95 A; A=2-136.
DR PDB; 4H9R; X-ray; 2.20 A; A=2-136.
DR PDB; 4H9S; X-ray; 2.60 A; A/B=2-136.
DR PDB; 4HGA; X-ray; 2.80 A; B=1-136.
DR PDB; 4L58; X-ray; 1.48 A; B=2-13.
DR PDBsum; 2L43; -.
DR PDBsum; 3ASK; -.
DR PDBsum; 3ASL; -.
DR PDBsum; 3AV2; -.
DR PDBsum; 3JVK; -.
DR PDBsum; 3MUK; -.
DR PDBsum; 3MUL; -.
DR PDBsum; 3QL9; -.
DR PDBsum; 3QLA; -.
DR PDBsum; 3QLC; -.
DR PDBsum; 4GNE; -.
DR PDBsum; 4GNF; -.
DR PDBsum; 4GNG; -.
DR PDBsum; 4GU0; -.
DR PDBsum; 4GUR; -.
DR PDBsum; 4GUS; -.
DR PDBsum; 4GY5; -.
DR PDBsum; 4H9N; -.
DR PDBsum; 4H9O; -.
DR PDBsum; 4H9P; -.
DR PDBsum; 4H9Q; -.
DR PDBsum; 4H9R; -.
DR PDBsum; 4H9S; -.
DR PDBsum; 4HGA; -.
DR PDBsum; 4L58; -.
DR ProteinModelPortal; P84243; -.
DR SMR; P84243; 17-136.
DR DIP; DIP-40046N; -.
DR IntAct; P84243; 30.
DR MINT; MINT-4825076; -.
DR STRING; 9606.ENSP00000254810; -.
DR PhosphoSite; P84243; -.
DR PaxDb; P84243; -.
DR PRIDE; P84243; -.
DR DNASU; 3020; -.
DR DNASU; 3021; -.
DR Ensembl; ENST00000254810; ENSP00000254810; ENSG00000132475.
DR Ensembl; ENST00000366813; ENSP00000355778; ENSG00000163041.
DR Ensembl; ENST00000366815; ENSP00000355780; ENSG00000163041.
DR Ensembl; ENST00000366816; ENSP00000355781; ENSG00000163041.
DR Ensembl; ENST00000586607; ENSP00000466020; ENSG00000132475.
DR Ensembl; ENST00000587560; ENSP00000468714; ENSG00000132475.
DR Ensembl; ENST00000589599; ENSP00000465813; ENSG00000132475.
DR GeneID; 3020; -.
DR GeneID; 3021; -.
DR KEGG; hsa:3020; -.
DR KEGG; hsa:3021; -.
DR UCSC; uc001hpw.3; human.
DR CTD; 3020; -.
DR CTD; 3021; -.
DR H-InvDB; HIX0135637; -.
DR HGNC; HGNC:4764; H3F3A.
DR HGNC; HGNC:4765; H3F3B.
DR HPA; CAB011481; -.
DR HPA; CAB037221; -.
DR HPA; HPA042570; -.
DR MIM; 601058; gene.
DR MIM; 601128; gene.
DR neXtProt; NX_P84243; -.
DR PharmGKB; PA29140; -.
DR eggNOG; COG2036; -.
DR HOVERGEN; HBG001172; -.
DR InParanoid; P84243; -.
DR KO; K11253; -.
DR OMA; QEATESY; -.
DR Reactome; REACT_111183; Meiosis.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_604; Hemostasis.
DR EvolutionaryTrace; P84243; -.
DR GeneWiki; H3F3A; -.
DR NextBio; 11966; -.
DR PRO; PR:P84243; -.
DR ArrayExpress; P84243; -.
DR Bgee; P84243; -.
DR CleanEx; HS_H3F3A; -.
DR CleanEx; HS_H3F3B; -.
DR Genevestigator; P84243; -.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0000786; C:nucleosome; IEA:UniProtKB-KW.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0007420; P:brain development; IEA:Ensembl.
DR GO; GO:0006334; P:nucleosome assembly; IEA:InterPro.
DR GO; GO:0009725; P:response to hormone stimulus; IEA:Ensembl.
DR Gene3D; 1.10.20.10; -; 1.
DR InterPro; IPR009072; Histone-fold.
DR InterPro; IPR007125; Histone_core_D.
DR InterPro; IPR000164; Histone_H3.
DR PANTHER; PTHR11426; PTHR11426; 1.
DR Pfam; PF00125; Histone; 1.
DR PRINTS; PR00622; HISTONEH3.
DR SMART; SM00428; H3; 1.
DR SUPFAM; SSF47113; SSF47113; 1.
DR PROSITE; PS00322; HISTONE_H3_1; 1.
DR PROSITE; PS00959; HISTONE_H3_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Chromosome; Citrullination;
KW Complete proteome; Direct protein sequencing; DNA-binding;
KW Methylation; Nucleosome core; Nucleus; Phosphoprotein;
KW Reference proteome; Ubl conjugation.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 136 Histone H3.3.
FT /FTId=PRO_0000221247.
FT MOD_RES 3 3 Asymmetric dimethylarginine; by PRMT6.
FT MOD_RES 4 4 Phosphothreonine; by GSG2.
FT MOD_RES 5 5 Allysine; alternate.
FT MOD_RES 5 5 N6,N6,N6-trimethyllysine; alternate.
FT MOD_RES 5 5 N6,N6-dimethyllysine; alternate.
FT MOD_RES 5 5 N6-acetyllysine; alternate.
FT MOD_RES 5 5 N6-crotonyl-L-lysine; alternate.
FT MOD_RES 5 5 N6-methyllysine; alternate.
FT MOD_RES 7 7 Phosphothreonine; by PKC.
FT MOD_RES 9 9 Citrulline; alternate.
FT MOD_RES 9 9 Symmetric dimethylarginine; by PRMT5;
FT alternate (By similarity).
FT MOD_RES 10 10 N6,N6,N6-trimethyllysine; alternate.
FT MOD_RES 10 10 N6,N6-dimethyllysine; alternate.
FT MOD_RES 10 10 N6-acetyllysine; alternate.
FT MOD_RES 10 10 N6-crotonyl-L-lysine; alternate.
FT MOD_RES 10 10 N6-methyllysine; alternate.
FT MOD_RES 11 11 Phosphoserine; by AURKB, AURKC, RPS6KA3,
FT RPS6KA4 and RPS6KA5.
FT MOD_RES 12 12 Phosphothreonine; by PKC.
FT MOD_RES 15 15 N6-acetyllysine.
FT MOD_RES 18 18 Asymmetric dimethylarginine; by CARM1;
FT alternate.
FT MOD_RES 18 18 Citrulline; alternate.
FT MOD_RES 19 19 N6-acetyllysine; alternate.
FT MOD_RES 19 19 N6-crotonyl-L-lysine; alternate.
FT MOD_RES 19 19 N6-methyllysine; alternate.
FT MOD_RES 24 24 N6-acetyllysine; alternate.
FT MOD_RES 24 24 N6-crotonyl-L-lysine; alternate.
FT MOD_RES 24 24 N6-methyllysine; alternate.
FT MOD_RES 28 28 N6,N6,N6-trimethyllysine; alternate.
FT MOD_RES 28 28 N6,N6-dimethyllysine; alternate.
FT MOD_RES 28 28 N6-acetyllysine; alternate.
FT MOD_RES 28 28 N6-crotonyl-L-lysine; alternate.
FT MOD_RES 28 28 N6-methyllysine; alternate.
FT MOD_RES 29 29 Phosphoserine; by AURKB, AURKC and
FT RPS6KA5.
FT MOD_RES 32 32 Phosphoserine.
FT MOD_RES 37 37 N6,N6,N6-trimethyllysine; alternate.
FT MOD_RES 37 37 N6,N6-dimethyllysine; alternate.
FT MOD_RES 37 37 N6-acetyllysine; alternate.
FT MOD_RES 37 37 N6-methyllysine; alternate.
FT MOD_RES 38 38 N6-methyllysine (By similarity).
FT MOD_RES 42 42 Phosphotyrosine.
FT MOD_RES 57 57 N6,N6,N6-trimethyllysine; alternate.
FT MOD_RES 57 57 N6-acetyllysine; alternate.
FT MOD_RES 57 57 N6-crotonyl-L-lysine; alternate.
FT MOD_RES 57 57 N6-methyllysine; by EHMT2; alternate.
FT MOD_RES 58 58 Phosphoserine.
FT MOD_RES 65 65 N6-methyllysine.
FT MOD_RES 80 80 N6,N6,N6-trimethyllysine; alternate (By
FT similarity).
FT MOD_RES 80 80 N6,N6-dimethyllysine; alternate.
FT MOD_RES 80 80 N6-acetyllysine; alternate.
FT MOD_RES 80 80 N6-methyllysine; alternate.
FT MOD_RES 81 81 Phosphothreonine.
FT MOD_RES 108 108 Phosphothreonine (By similarity).
FT MOD_RES 116 116 N6-acetyllysine.
FT MOD_RES 123 123 N6-acetyllysine; alternate.
FT MOD_RES 123 123 N6-methyllysine; alternate.
FT CONFLICT 9 9 R -> L (in Ref. 7; AAH81561).
FT STRAND 4 6
FT HELIX 8 10
FT STRAND 45 47
FT HELIX 49 59
FT HELIX 65 79
FT STRAND 80 82
FT STRAND 84 86
FT HELIX 87 110
FT STRAND 118 120
FT HELIX 122 132
SQ SEQUENCE 136 AA; 15328 MW; 5158ED279E6F9E1C CRC64;
MARTKQTARK STGGKAPRKQ LATKAARKSA PSTGGVKKPH RYRPGTVALR EIRRYQKSTE
LLIRKLPFQR LVREIAQDFK TDLRFQSAAI GALQEASEAY LVGLFEDTNL CAIHAKRVTI
MPKDIQLARR IRGERA
//
MIM
601058
*RECORD*
*FIELD* NO
601058
*FIELD* TI
*601058 H3 HISTONE, FAMILY 3B; H3F3B
;;H3.3B
*FIELD* TX
DESCRIPTION
Histones are the basic nuclear proteins responsible for the nucleosome
read morestructure of the chromosomal fiber in eukaryotes. Five classes of
histone genes have been reported, all of which are involved in
chromosome structure. Some classes are expressed only during S phase,
while others are replication independent. The latter are referred to as
replacement histones and are expressed in quiescent or terminally
differentiated cells. H3.3 is a replacement histone that is encoded by 2
distinct replication-independent genes, H3.3A (H3F3A; 601128) and H3.3B
(H3F3B). The proteins encoded by the H3.3A and H3.3B genes are identical
(Albig et al., 1995).
For additional background information on histones, histone gene
clusters, and the H3 histone family, see HIST1H3A (602810).
CLONING
Albig et al. (1995) used a histone H1 probe to identify a full-length
cDNA, designated H3.3B by them, from a human testicular library. The
amino acid sequence of H3.3B is identical to that of H3.3A, as well as
to the amino acid sequences of H3.3 homologs in other species, including
Drosophila. However, the nucleotide sequences of H3.3A and H3.3B differ
substantially, especially in the 5-prime and 3-prime UTRs. Northern blot
analysis detected 1.8- and 1.4-kb mRNAs, which differ due to alternative
use of polyadenylation signals, in RNA from testis and the HEK293
embryonal kidney tumor cell line.
Using an RNase protections assay, Witt et al. (1997) showed variable
expression of 1.4- and 1.8-kb H3.3B transcripts in human tissues and
cell lines, with the 1.8-kb transcript predominating. They reported that
H3.3a was basally expressed in mouse testis, whereas H3.3b was expressed
in a stage-specific manner.
Using Northern blot analysis, Frank et al. (2003) assayed for expression
of the replacement histones H3.3A and H3.3B and the cell cycle-dependent
histone H3/m (HIST2H3C; 142780) in human tissues and cell lines. All 6
cell lines expressed H3.3A, H3.3B, and H3/m at high levels. Conversely,
fetal liver predominantly expressed H3/m, likely due to its rapid cell
growth, whereas adult liver, kidney, and heart predominantly expressed
H3.3A and H3.3B. The H3.3B transcript was detected at 1.4 and 1.8 kb.
GENE STRUCTURE
Albig et al. (1995) isolated the H3.3B gene and found that it spans
approximately 2.5 kb. It has 4 exons, the first of which is noncoding,
and exhibits features characteristic of a histone H3.3 gene.
Witt et al. (1997) identified 6 CCAAT boxes, a conserved functional
octamer element, a CRE/TRE element, and a TATA box within the proximal
promoter region of the H3.3B gene.
Frank et al. (2003) stated that the 3-prime end of the H3.3B gene
contains 3 transcriptional termination signals.
MAPPING
Albig et al. (1995) mapped the H3F3B gene by fluorescence in situ
hybridization to chromosome 17q25.
GENE FUNCTION
See H3F3A (601128) for functional information on H3.3 histone.
See HIST1H3A (602810) for functional information on the H3 histone
family.
MOLECULAR GENETICS
Behjati et al. (2013) reported exquisite tumor type specificity for
different histone H3.3 driver alterations. In 73 of 77 cases (95%) of
chondroblastoma, Behjati et al. (2013) found K36M alterations
predominantly encoded by H3F3B, which is 1 of 2 genes for histone H3.3.
In contrast, in 92% (49 of 53) of giant cell tumors of bone, Behjati et
al. (2013) found histone H3.3 alterations exclusively in H3F3A (601128),
leading to G34W or, in 1 case, G34L alterations. The mutations were
restricted to the stromal cell population and were not detected in
osteoclasts or their precursors. In the context of previously reported
H3F3A mutations encoding K27M and G34R or G34V alterations in childhood
brain tumors, a picture of tumor type specificity for histone H3.3
driver alterations emerged, indicating that histone H3.3 residues,
mutations, and genes have distinct functions.
*FIELD* RF
1. Albig, W.; Bramlage, B.; Gruber, K.; Klobeck, H.-G.; Kunz, J.;
Doenecke, D.: The human replacement histone H3.3B gene (H3F3B). Genomics 30:
264-272, 1995.
2. Behjati, S.; Tarpey, P. S.; Presneau, N.; Scheipl, S.; Pillay,
N.; Van Loo, P.; Wedge, D. C.; Cooke, S. L.; Gundem, G.; Davies, H.;
Nik-Zainal, S.; Martin, S.; and 17 others: Distinct H3F3A and H3F3B
driver mutations define chondroblastoma and giant cell tumor of bone. Nature
Genet. 45 1479-1482, 2013.
3. Frank, D.; Doenecke, D.; Albig, W.: Differential expression of
human replacement and cell cycle dependent H3 histone genes. Gene 312:
135-143, 2003.
4. Witt, O.; Albig, W.; Doenecke, D.: Transcriptional regulation
of the human replacement histone gene H3.3B. FEBS Lett. 408: 255-260,
1997.
*FIELD* CN
Ada Hamosh - updated: 1/14/2014
Patricia A. Hartz - updated: 2/6/2013
Matthew B. Gross - updated: 2/4/2013
Matthew B. Gross - updated: 5/17/2010
Rebekah S. Rasooly - updated: 7/8/1998
*FIELD* CD
Alan F. Scott: 2/11/1996
*FIELD* ED
alopez: 01/14/2014
alopez: 1/14/2014
mgross: 2/6/2013
mgross: 2/5/2013
mgross: 2/4/2013
mgross: 5/17/2010
alopez: 4/14/2010
terry: 4/13/2010
alopez: 4/6/2010
alopez: 7/9/1998
alopez: 7/8/1998
mark: 9/22/1996
mark: 2/11/1996
*RECORD*
*FIELD* NO
601058
*FIELD* TI
*601058 H3 HISTONE, FAMILY 3B; H3F3B
;;H3.3B
*FIELD* TX
DESCRIPTION
Histones are the basic nuclear proteins responsible for the nucleosome
read morestructure of the chromosomal fiber in eukaryotes. Five classes of
histone genes have been reported, all of which are involved in
chromosome structure. Some classes are expressed only during S phase,
while others are replication independent. The latter are referred to as
replacement histones and are expressed in quiescent or terminally
differentiated cells. H3.3 is a replacement histone that is encoded by 2
distinct replication-independent genes, H3.3A (H3F3A; 601128) and H3.3B
(H3F3B). The proteins encoded by the H3.3A and H3.3B genes are identical
(Albig et al., 1995).
For additional background information on histones, histone gene
clusters, and the H3 histone family, see HIST1H3A (602810).
CLONING
Albig et al. (1995) used a histone H1 probe to identify a full-length
cDNA, designated H3.3B by them, from a human testicular library. The
amino acid sequence of H3.3B is identical to that of H3.3A, as well as
to the amino acid sequences of H3.3 homologs in other species, including
Drosophila. However, the nucleotide sequences of H3.3A and H3.3B differ
substantially, especially in the 5-prime and 3-prime UTRs. Northern blot
analysis detected 1.8- and 1.4-kb mRNAs, which differ due to alternative
use of polyadenylation signals, in RNA from testis and the HEK293
embryonal kidney tumor cell line.
Using an RNase protections assay, Witt et al. (1997) showed variable
expression of 1.4- and 1.8-kb H3.3B transcripts in human tissues and
cell lines, with the 1.8-kb transcript predominating. They reported that
H3.3a was basally expressed in mouse testis, whereas H3.3b was expressed
in a stage-specific manner.
Using Northern blot analysis, Frank et al. (2003) assayed for expression
of the replacement histones H3.3A and H3.3B and the cell cycle-dependent
histone H3/m (HIST2H3C; 142780) in human tissues and cell lines. All 6
cell lines expressed H3.3A, H3.3B, and H3/m at high levels. Conversely,
fetal liver predominantly expressed H3/m, likely due to its rapid cell
growth, whereas adult liver, kidney, and heart predominantly expressed
H3.3A and H3.3B. The H3.3B transcript was detected at 1.4 and 1.8 kb.
GENE STRUCTURE
Albig et al. (1995) isolated the H3.3B gene and found that it spans
approximately 2.5 kb. It has 4 exons, the first of which is noncoding,
and exhibits features characteristic of a histone H3.3 gene.
Witt et al. (1997) identified 6 CCAAT boxes, a conserved functional
octamer element, a CRE/TRE element, and a TATA box within the proximal
promoter region of the H3.3B gene.
Frank et al. (2003) stated that the 3-prime end of the H3.3B gene
contains 3 transcriptional termination signals.
MAPPING
Albig et al. (1995) mapped the H3F3B gene by fluorescence in situ
hybridization to chromosome 17q25.
GENE FUNCTION
See H3F3A (601128) for functional information on H3.3 histone.
See HIST1H3A (602810) for functional information on the H3 histone
family.
MOLECULAR GENETICS
Behjati et al. (2013) reported exquisite tumor type specificity for
different histone H3.3 driver alterations. In 73 of 77 cases (95%) of
chondroblastoma, Behjati et al. (2013) found K36M alterations
predominantly encoded by H3F3B, which is 1 of 2 genes for histone H3.3.
In contrast, in 92% (49 of 53) of giant cell tumors of bone, Behjati et
al. (2013) found histone H3.3 alterations exclusively in H3F3A (601128),
leading to G34W or, in 1 case, G34L alterations. The mutations were
restricted to the stromal cell population and were not detected in
osteoclasts or their precursors. In the context of previously reported
H3F3A mutations encoding K27M and G34R or G34V alterations in childhood
brain tumors, a picture of tumor type specificity for histone H3.3
driver alterations emerged, indicating that histone H3.3 residues,
mutations, and genes have distinct functions.
*FIELD* RF
1. Albig, W.; Bramlage, B.; Gruber, K.; Klobeck, H.-G.; Kunz, J.;
Doenecke, D.: The human replacement histone H3.3B gene (H3F3B). Genomics 30:
264-272, 1995.
2. Behjati, S.; Tarpey, P. S.; Presneau, N.; Scheipl, S.; Pillay,
N.; Van Loo, P.; Wedge, D. C.; Cooke, S. L.; Gundem, G.; Davies, H.;
Nik-Zainal, S.; Martin, S.; and 17 others: Distinct H3F3A and H3F3B
driver mutations define chondroblastoma and giant cell tumor of bone. Nature
Genet. 45 1479-1482, 2013.
3. Frank, D.; Doenecke, D.; Albig, W.: Differential expression of
human replacement and cell cycle dependent H3 histone genes. Gene 312:
135-143, 2003.
4. Witt, O.; Albig, W.; Doenecke, D.: Transcriptional regulation
of the human replacement histone gene H3.3B. FEBS Lett. 408: 255-260,
1997.
*FIELD* CN
Ada Hamosh - updated: 1/14/2014
Patricia A. Hartz - updated: 2/6/2013
Matthew B. Gross - updated: 2/4/2013
Matthew B. Gross - updated: 5/17/2010
Rebekah S. Rasooly - updated: 7/8/1998
*FIELD* CD
Alan F. Scott: 2/11/1996
*FIELD* ED
alopez: 01/14/2014
alopez: 1/14/2014
mgross: 2/6/2013
mgross: 2/5/2013
mgross: 2/4/2013
mgross: 5/17/2010
alopez: 4/14/2010
terry: 4/13/2010
alopez: 4/6/2010
alopez: 7/9/1998
alopez: 7/8/1998
mark: 9/22/1996
mark: 2/11/1996
MIM
601128
*RECORD*
*FIELD* NO
601128
*FIELD* TI
*601128 H3 HISTONE, FAMILY 3A; H3F3A
;;H3F3;;
H3.3A
*FIELD* TX
DESCRIPTION
Histones are the basic nuclear proteins responsible for the nucleosome
read morestructure within the chromosomal fiber in eukaryotes. Five classes of
histone genes have been reported. Some classes are expressed only during
S phase, while others are replication independent. The latter are
referred to as replacement histones and are expressed in quiescent or
terminally differentiated cells. H3.3 is a replacement histone that is
encoded by 2 distinct replication-independent genes, H3.3A (H3F3A) and
H3.3B (H3F3B; 601058). The proteins encoded by the H3.3A and H3.3B genes
are identical (summary by Wells et al. (1987) and Albig et al. (1995)).
For additional background information on histones, histone gene
clusters, and the H3 histone family, see HIST1H3A (602810).
CLONING
Using an H3.3 pseudogene cDNA to probe a human fibroblast cDNA library,
Wells and Kedes (1985) cloned H3.3. The transcript contains a long
3-prime poly(A) tail, and the deduced protein contains 135 amino acids.
The H3.3 protein has 5 amino acid changes compared with H3.1 (see
602812), but their nucleotide sequences are more divergent. Northern
blot analysis detected a transcript of about 1.2 kb in HeLa cell poly(A)
RNA.
Chalmers and Wells (1990) showed that the rabbit H3.3a 3-prime
untranslated region is 94% similar to the human sequence of Wells and
Kedes (1985), indicating that evolutionary conservation extends beyond
the coding region.
Witt et al. (1997) noted that although the H3.3A and H3.3B proteins are
identical, their nucleotide coding sequences and flanking portions
differ. They reported that H3.3a was basally expressed in mouse testis,
whereas H3.3b was expressed in a stage-specific manner.
Using Northern blot analysis, Frank et al. (2003) assayed for expression
of the replacement histones H3.3A and H3.3B and the cell cycle-dependent
histone H3/m (HIST2H3C; 142780) in human tissues and cell lines. All 6
cell lines expressed H3.3A, H3.3B, and H3/m at high levels. Conversely,
fetal liver predominantly expressed H3/m, likely due to its rapid cell
growth, whereas adult liver, kidney, and heart predominantly expressed
H3.3A and H3.3B. The H3.3A transcript was detected at 1.0 kb.
GENE STRUCTURE
Wells and Kedes (1985) determined that the 5-prime UTR of the H3F3A gene
is GC rich (75%).
Wells et al. (1987) determined that the H3F3A gene contains 4 exons and
spans 8.8 kb. The first exon is noncoding. The 5-prime end contains
noncanonical TATA and CCAAT boxes and an SP1 (189906)-binding GC box.
The 3-prime end contains 2 potential polyadenylation signals and is
highly conserved, sharing 85% identity with the chicken ortholog.
MAPPING
By analysis of a somatic cell hybrid panel and by inclusion within a YAC
from that region, Lin and Wells (1997) mapped the H3F3A gene to
chromosome 1q41.
GENE FUNCTION
See HIST1H3A (602810) for functional information on the H3 histone
family.
- H3.3 Histone
Hake et al. (2006) noted that most studies on expression or
posttranslational modifications of H3 histones do not differentiate
between the H3.1 (see 602810), H3.2 (HIST2H3C; 142780), and H3.3
proteins, in part due to their high degree of amino acid identity. By
quantitative PCR of 5 human cell lines, they found that the 9 H3.1
genes, 1 H3.2 gene, and 2 H3.3 genes examined were expressed in a cell
line-specific manner. All 3 types of H3 genes were highly expressed
during S phase in human cell lines, whereas the H3.3 genes were also
highly expressed outside of S phase, consistent with their status as
replication-independent genes. Using a combination of isotopic labeling
and quantitative tandem mass spectrometry, Hake et al. (2006) showed
that the H3.1, H3.2, and H3.3 proteins differed in their
posttranslational modifications. H3.1 was enriched in marks associated
with both gene activation and gene silencing, H3.2 was enriched in
repressive marks associated with gene silencing and the formation of
facultative heterochromatin, and H3.3 was enriched in marks associated
with transcriptional activation. Hake et al. (2006) concluded that H3.1,
H3.2, and H3.3 likely have unique functions and should not be treated as
equivalent proteins.
Jin et al. (2009) characterized the genomewide distribution of
nucleosome core particles containing H3.3 and/or H2A.Z (H2AFZ; 142763)
in HeLa cells. They found that highly labile particles containing both
H3.3 and H2A.Z were enriched at active promoters, enhancers, and
insulator regions. Nucleosomes containing H3.3, but not H2A.Z, were also
relatively unstable and were detected along the transcribed region of
genes and at transcriptional stop sites. Jin et al. (2009) suggested
that unstable particles containing both H3.3 and H2A.Z may serve as
place holders that are easily displaced by transcription factors. They
proposed that unstable particles containing only H3.3 along the
transcribed portions of genes may accommodate the passage of RNA
polymerase.
Xu et al. (2010) reported that significant amounts of histone H3.3-H4
(see 602822) tetramers split in vivo, whereas most H3.1 (see 602810)-H4
tetramers remain intact during mitotic division. Inhibiting DNA
replication-dependent deposition greatly reduced the level of splitting
events, which suggested that (i) the replication-independent H3.3
deposition pathway proceeds largely by cooperatively incorporating 2 new
H3.3-H4 dimers, and (ii) the majority of splitting events occur during
replication-dependent deposition. Xu et al. (2010) concluded that
'silent' histone modifications within large heterochromatic regions are
maintained by copying modifications from neighboring preexisting
histones without the need for H3-H4 splitting events.
Talbert and Henikoff (2010) reviewed the assembly of canonical
nucleosomes, which is thought to begin with a tetramer of 2 H3 molecules
and 2 H4 molecules held together by strong bonds between the H3
molecules. H3.1 is the major canonical H3 assembled into chromatin by
the histone chaperone CAF1 (see 601246) complex during DNA replication
and repair. The replacement histone H3.3 is assembled by the histone
regulator A (HIRA; 600237) complex independently of DNA synthesis.
BIOCHEMICAL FEATURES
- Crystal Structure
Elsasser et al. (2012) reported the crystal structures of the DAXX
(603186) histone-binding domain with a histone H3.3-H4 (see 602822)
dimer, including mutants within DAXX and H3.3, together with in vitro
and in vivo functional studies that elucidated the principles underlying
H3.3 recognition specificity. Occupying 40% of the histone
surface-accessible area, DAXX wraps around the H3.3-H4 dimer, with
complex formation accompanied by structural transitions in the H3.3-H4
histone fold. DAXX uses an extended alpha-helical conformation to
compete with major interhistone, DNA, and ASF1 interaction sites.
Elsasser et al. (2012) concluded that their structural studies
identified recognition elements that read out H3.3-specific residues,
and functional studies addressed the contribution of gly90 in H3.3 and
glu225 in DAXX to chaperone-mediated H3.3 variant recognition
specificity.
MOLECULAR GENETICS
Schwartzentruber et al. (2012) sequenced the exomes of 48 pediatric
glioblastoma (137800) samples. Somatic mutations in the H3.3-ATRX
(300032)-DAXX (603186) chromatin remodeling pathway were identified in
44% of tumors (21 of 48). Recurrent mutations in H3F3A, which encodes
the replication-independent histone-3 variant H3.3, were observed in 31%
of tumors, and led to amino acid substitutions at 2 critical positions
within the histone tail (K27M, G34R/G34V) involved in key regulatory
posttranslational modifications. Mutations in ATRX and DAXX, encoding 2
subunits of a chromatin remodeling complex required for H3.3
incorporation at pericentric heterochromatin and telomeres, were
identified in 31% of samples overall, and in 100% of tumors harboring a
G34R or G34V H3.3 mutation. Somatic TP53 (191170) mutations were
identified in 54% of all cases, and in 86% of samples with H3F3A and/or
ATRX mutations. Screening of a large cohort of gliomas of various grades
and histologies (n = 784) showed H3F3A mutations to be specific to
glioblastoma multiforme and highly prevalent in children and young
adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was
strongly associated with alternative lengthening of telomeres and
specific gene expression profiles. Schwartzentruber et al. (2012) stated
that this was the first report to highlight recurrent mutations in a
regulatory histone in humans, and that their data suggested that defects
of the chromatin architecture underlie pediatric and young adult
glioblastoma multiforme pathogenesis.
Wu et al. (2012) reported that a K27M mutation occurring in either H3F3A
or HIST1H3B (602819) was observed in 78% of diffuse intrinsic pontine
gliomas (DIPGs) and 22% of non-brain-stem gliomas.
Lewis et al. (2013) reported that human DIPGs containing the K27M
mutation in either histone H3.3 (H3F3A) or H3.1 (HIST1H3B) display
significantly lower overall amounts of H3 with trimethylated lysine-27
(H3K27me3) and that histone H3K27M transgenes are sufficient to reduce
the amounts of H3K27me3 in vitro and in vivo. Lewis et al. (2013) found
that H3K27M inhibits the enzymatic activity of the Polycomb repressive
complex-2 (PRC2) through interaction with the EZH2 (601573) subunit. In
addition, transgenes containing lysine-to-methionine substitutions at
other known methylated lysines (H3K9 and H3K36) are sufficient to cause
specific reduction in methylation through inhibition of SET domain
enzymes. Lewis et al. (2013) proposed that K-to-M substitutions may
represent a mechanism to alter epigenetic states in a variety of
pathologies.
Behjati et al. (2013) reported exquisite tumor type specificity for
different histone H3.3 driver alterations. In 73 of 77 cases (95%) of
chondroblastoma, Behjati et al. (2013) found K36M alterations
predominantly encoded by H3F3B (601058), which is 1 of 2 genes for
histone H3.3. In contrast, in 92% (49 of 53) of giant cell tumors of
bone, Behjati et al. (2013) found histone H3.3 alterations exclusively
in H3F3A, leading to G34W or, in 1 case, G34L alterations. The mutations
were restricted to the stromal cell population and were not detected in
osteoclasts or their precursors. In the context of previously reported
H3F3A mutations encoding K27M and G34R or G34V alterations in childhood
brain tumors, a picture of tumor type specificity for histone H3.3
driver alterations emerged, indicating that histone H3.3 residues,
mutations, and genes have distinct functions.
*FIELD* RF
1. Albig, W.; Bramlage, B.; Gruber, K.; Klobeck, H.-G.; Kunz, J.;
Doenecke, D.: The human replacement histone H3.3B gene (H3F3B). Genomics 30:
264-272, 1995.
2. Behjati, S.; Tarpey, P. S.; Presneau, N.; Scheipl, S.; Pillay,
N.; Van Loo, P.; Wedge, D. C.; Cooke, S. L.; Gundem, G.; Davies, H.;
Nik-Zainal, S.; Martin, S.; and 17 others: Distinct H3F3A and H3F3B
driver mutations define chondroblastoma and giant cell tumor of bone. Nature
Genet. 45 1479-1482, 2013.
3. Chalmers, M.; Wells, D.: Extreme sequence conservation characterizes
the rabbit H3.3A histone cDNA. Nucleic Acids Res. 18: 3075, 1990.
4. Elsasser, S. J.; Huang, H.; Lewis, P. W.; Chin, J. W.; Allis, C.
D.; Patel, D. J.: DAXX envelops a histone H3.3-H4 dimer for H3.3-specific
recognition. Nature 491: 560-565, 2012.
5. Frank, D.; Doenecke, D.; Albig, W.: Differential expression of
human replacement and cell cycle dependent H3 histone genes. Gene 312:
135-143, 2003.
6. Hake, S. B.; Garcia, B. A.; Duncan, E. M.; Kauer, M.; Dellaire,
G.; Shabanowitz, J.; Bazett-Jones, D. P.; Allis, C. D.; Hunt, D. F.
: Expression patterns and post-translational modifications associated
with mammalian histone H3 variants. J. Biol. Chem. 281: 559-568,
2006.
7. Jin, C.; Zang, C.; Wei, G.; Cui, K.; Peng, W.; Zhao, K.; Felsenfeld,
G.: H3.3/H2A.Z double variant-containing nucleosomes mark 'nucleosome-free
regions' of active promoters and other regulatory regions. Nature
Genet. 41: 941-945, 2009.
8. Lewis, P. W.; Muller, M. M.; Koletsky, M. S.; Cordero, F.; Lin,
S.; Banaszynski, L. A.; Garcia, B. A.; Muir, T. W.; Becher, O. J.;
Allis, C. D.: Inhibition of PRC2 activity by a gain-of-function H3
mutation found in pediatric glioblastoma. Science 340: 857-861,
2013.
9. Lin, X.; Wells, D. E.: Localization of the human H3F3A histone
gene to 1q41, outside of the normal histone gene clusters. Genomics 46:
526-528, 1997.
10. Schwartzentruber, J.; Korshunov, A; Liu, X.-Y.; Jones, D. T. W.;
Pfaff, E.; Jacob, K.; Sturm, D.; Fontebasso, A. M.; Quang, D.-A. K.;
Tonjes, M.; Hovestadt, V.; Albrecht, S.; and 50 others: Driver
mutations in histone H3.3 and chromatin remodelling genes in paediatric
glioblastoma. Nature 482: 226-231, 2012. Note: Erratum: Nature 484:
130 only, 2012.
11. Talbert, P. B.; Henikoff, S.: Histone variants--ancient wrap
artists of the epigenome. Nature Rev. Molec. Cell Biol. 11: 264-275,
2010.
12. Wells, D.; Hoffman, D.; Kedes, L.: Unusual structure, evolutionary
conservation of non-coding sequences and numerous pseudogenes characterize
the H3.3 histone multigene family. Nucleic Acids Res. 15: 2871-2889,
1987.
13. Wells, D.; Kedes, L.: Structure of a human histone cDNA: evidence
that basally expressed histone genes have intervening sequences and
encode polyadenylated mRNAs. Proc. Nat. Acad. Sci. 82: 2834-2838,
1985.
14. Witt, O.; Albig, W.; Doenecke, D.: Transcriptional regulation
of the human replacement histone gene H3.3B. FEBS Lett. 408: 255-260,
1997.
15. Wu, G.; Broniscer, A.; McEachron, T. A.; Lu, C.; Paugh, B. S.;
Becksfort, J.; Qu, C.; Ding, L.; Huether, R.; Parker, M.; Zhang, J.;
Gajjar, A.; and 9 others: Somatic histone H3 alterations in pediatric
diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nature
Genet 44: 251-253, 2012.
16. Xu, M.; Long, C.; Chen, X.; Huang, C.; Chen, S.; Zhu, B.: Partitioning
of histone H3-H4 tetramers during DNA replication-dependent chromatin
assembly. Science 328: 94-98, 2010.
*FIELD* CN
Ada Hamosh - updated: 01/14/2014
Ada Hamosh - updated: 6/24/2013
Patricia A. Hartz - updated: 2/6/2013
Matthew B. Gross - updated: 2/4/2013
Ada Hamosh - updated: 12/13/2012
Ada Hamosh - updated: 9/6/2012
Ada Hamosh - updated: 8/29/2012
Ada Hamosh - updated: 3/7/2012
Patricia A. Hartz - updated: 5/14/2010
Patricia A. Hartz - updated: 5/12/2010
Ada Hamosh - updated: 4/28/2010
Ada Hamosh - updated: 4/13/2010
Ada Hamosh - updated: 3/11/2010
Ada Hamosh - updated: 2/1/2010
Ada Hamosh - updated: 10/19/2009
Ada Hamosh - updated: 9/16/2009
Ada Hamosh - updated: 9/9/2009
Ada Hamosh - updated: 8/10/2009
Cassandra L. Kniffin - updated: 6/8/2009
Ada Hamosh - updated: 6/4/2009
Ada Hamosh - updated: 5/23/2008
Ada Hamosh - updated: 3/26/2008
Ada Hamosh - updated: 3/6/2008
Ada Hamosh - updated: 2/21/2008
Ada Hamosh - updated: 11/26/2007
Ada Hamosh - updated: 8/28/2007
Ada Hamosh - updated: 8/13/2007
Ada Hamosh - updated: 8/15/2006
George E. Tiller - updated: 1/31/2006
Ada Hamosh - updated: 1/12/2006
Ada Hamosh - updated: 11/3/2005
Ada Hamosh - updated: 10/25/2005
Ada Hamosh - updated: 8/18/2005
Ada Hamosh - updated: 12/15/2004
Ada Hamosh - updated: 6/17/2003
Ada Hamosh - updated: 4/15/2003
Ada Hamosh - updated: 11/20/2002
Stylianos E. Antonarakis - updated: 1/7/2002
Ada Hamosh - updated: 8/14/2001
Ada Hamosh - updated: 8/5/1999
Rebekah S. Rasooly - updated: 7/8/1998
*FIELD* CD
Alan F. Scott: 3/18/1996
*FIELD* ED
alopez: 01/14/2014
alopez: 6/24/2013
mgross: 2/8/2013
mgross: 2/6/2013
mgross: 2/4/2013
alopez: 12/21/2012
terry: 12/13/2012
alopez: 9/7/2012
terry: 9/6/2012
alopez: 9/4/2012
terry: 8/29/2012
terry: 5/22/2012
mgross: 5/3/2012
terry: 5/1/2012
carol: 4/11/2012
alopez: 3/12/2012
terry: 3/7/2012
terry: 4/20/2011
carol: 7/29/2010
mgross: 5/17/2010
terry: 5/14/2010
terry: 5/12/2010
alopez: 4/29/2010
terry: 4/28/2010
alopez: 4/14/2010
terry: 4/13/2010
carol: 4/5/2010
alopez: 3/11/2010
alopez: 2/1/2010
alopez: 1/27/2010
terry: 1/15/2010
alopez: 11/9/2009
alopez: 10/26/2009
terry: 10/19/2009
alopez: 9/22/2009
terry: 9/16/2009
terry: 9/9/2009
alopez: 8/19/2009
mgross: 8/10/2009
terry: 8/10/2009
wwang: 6/17/2009
ckniffin: 6/8/2009
alopez: 6/4/2009
joanna: 6/2/2009
terry: 5/19/2009
alopez: 6/2/2008
terry: 5/23/2008
alopez: 3/26/2008
alopez: 3/25/2008
terry: 3/6/2008
carol: 2/29/2008
terry: 2/21/2008
alopez: 11/29/2007
terry: 11/26/2007
alopez: 9/7/2007
terry: 8/28/2007
carol: 8/15/2007
terry: 8/13/2007
carol: 8/15/2006
wwang: 1/31/2006
alopez: 1/13/2006
terry: 1/12/2006
alopez: 11/7/2005
terry: 11/3/2005
alopez: 10/26/2005
terry: 10/25/2005
alopez: 8/23/2005
terry: 8/18/2005
alopez: 12/15/2004
alopez: 6/19/2003
terry: 6/17/2003
alopez: 4/17/2003
terry: 4/15/2003
cwells: 11/20/2002
terry: 11/18/2002
mgross: 1/7/2002
alopez: 8/20/2001
terry: 8/14/2001
alopez: 8/5/1999
alopez: 8/26/1998
alopez: 7/8/1998
mark: 9/22/1996
terry: 3/26/1996
mark: 3/19/1996
mark: 3/18/1996
*RECORD*
*FIELD* NO
601128
*FIELD* TI
*601128 H3 HISTONE, FAMILY 3A; H3F3A
;;H3F3;;
H3.3A
*FIELD* TX
DESCRIPTION
Histones are the basic nuclear proteins responsible for the nucleosome
read morestructure within the chromosomal fiber in eukaryotes. Five classes of
histone genes have been reported. Some classes are expressed only during
S phase, while others are replication independent. The latter are
referred to as replacement histones and are expressed in quiescent or
terminally differentiated cells. H3.3 is a replacement histone that is
encoded by 2 distinct replication-independent genes, H3.3A (H3F3A) and
H3.3B (H3F3B; 601058). The proteins encoded by the H3.3A and H3.3B genes
are identical (summary by Wells et al. (1987) and Albig et al. (1995)).
For additional background information on histones, histone gene
clusters, and the H3 histone family, see HIST1H3A (602810).
CLONING
Using an H3.3 pseudogene cDNA to probe a human fibroblast cDNA library,
Wells and Kedes (1985) cloned H3.3. The transcript contains a long
3-prime poly(A) tail, and the deduced protein contains 135 amino acids.
The H3.3 protein has 5 amino acid changes compared with H3.1 (see
602812), but their nucleotide sequences are more divergent. Northern
blot analysis detected a transcript of about 1.2 kb in HeLa cell poly(A)
RNA.
Chalmers and Wells (1990) showed that the rabbit H3.3a 3-prime
untranslated region is 94% similar to the human sequence of Wells and
Kedes (1985), indicating that evolutionary conservation extends beyond
the coding region.
Witt et al. (1997) noted that although the H3.3A and H3.3B proteins are
identical, their nucleotide coding sequences and flanking portions
differ. They reported that H3.3a was basally expressed in mouse testis,
whereas H3.3b was expressed in a stage-specific manner.
Using Northern blot analysis, Frank et al. (2003) assayed for expression
of the replacement histones H3.3A and H3.3B and the cell cycle-dependent
histone H3/m (HIST2H3C; 142780) in human tissues and cell lines. All 6
cell lines expressed H3.3A, H3.3B, and H3/m at high levels. Conversely,
fetal liver predominantly expressed H3/m, likely due to its rapid cell
growth, whereas adult liver, kidney, and heart predominantly expressed
H3.3A and H3.3B. The H3.3A transcript was detected at 1.0 kb.
GENE STRUCTURE
Wells and Kedes (1985) determined that the 5-prime UTR of the H3F3A gene
is GC rich (75%).
Wells et al. (1987) determined that the H3F3A gene contains 4 exons and
spans 8.8 kb. The first exon is noncoding. The 5-prime end contains
noncanonical TATA and CCAAT boxes and an SP1 (189906)-binding GC box.
The 3-prime end contains 2 potential polyadenylation signals and is
highly conserved, sharing 85% identity with the chicken ortholog.
MAPPING
By analysis of a somatic cell hybrid panel and by inclusion within a YAC
from that region, Lin and Wells (1997) mapped the H3F3A gene to
chromosome 1q41.
GENE FUNCTION
See HIST1H3A (602810) for functional information on the H3 histone
family.
- H3.3 Histone
Hake et al. (2006) noted that most studies on expression or
posttranslational modifications of H3 histones do not differentiate
between the H3.1 (see 602810), H3.2 (HIST2H3C; 142780), and H3.3
proteins, in part due to their high degree of amino acid identity. By
quantitative PCR of 5 human cell lines, they found that the 9 H3.1
genes, 1 H3.2 gene, and 2 H3.3 genes examined were expressed in a cell
line-specific manner. All 3 types of H3 genes were highly expressed
during S phase in human cell lines, whereas the H3.3 genes were also
highly expressed outside of S phase, consistent with their status as
replication-independent genes. Using a combination of isotopic labeling
and quantitative tandem mass spectrometry, Hake et al. (2006) showed
that the H3.1, H3.2, and H3.3 proteins differed in their
posttranslational modifications. H3.1 was enriched in marks associated
with both gene activation and gene silencing, H3.2 was enriched in
repressive marks associated with gene silencing and the formation of
facultative heterochromatin, and H3.3 was enriched in marks associated
with transcriptional activation. Hake et al. (2006) concluded that H3.1,
H3.2, and H3.3 likely have unique functions and should not be treated as
equivalent proteins.
Jin et al. (2009) characterized the genomewide distribution of
nucleosome core particles containing H3.3 and/or H2A.Z (H2AFZ; 142763)
in HeLa cells. They found that highly labile particles containing both
H3.3 and H2A.Z were enriched at active promoters, enhancers, and
insulator regions. Nucleosomes containing H3.3, but not H2A.Z, were also
relatively unstable and were detected along the transcribed region of
genes and at transcriptional stop sites. Jin et al. (2009) suggested
that unstable particles containing both H3.3 and H2A.Z may serve as
place holders that are easily displaced by transcription factors. They
proposed that unstable particles containing only H3.3 along the
transcribed portions of genes may accommodate the passage of RNA
polymerase.
Xu et al. (2010) reported that significant amounts of histone H3.3-H4
(see 602822) tetramers split in vivo, whereas most H3.1 (see 602810)-H4
tetramers remain intact during mitotic division. Inhibiting DNA
replication-dependent deposition greatly reduced the level of splitting
events, which suggested that (i) the replication-independent H3.3
deposition pathway proceeds largely by cooperatively incorporating 2 new
H3.3-H4 dimers, and (ii) the majority of splitting events occur during
replication-dependent deposition. Xu et al. (2010) concluded that
'silent' histone modifications within large heterochromatic regions are
maintained by copying modifications from neighboring preexisting
histones without the need for H3-H4 splitting events.
Talbert and Henikoff (2010) reviewed the assembly of canonical
nucleosomes, which is thought to begin with a tetramer of 2 H3 molecules
and 2 H4 molecules held together by strong bonds between the H3
molecules. H3.1 is the major canonical H3 assembled into chromatin by
the histone chaperone CAF1 (see 601246) complex during DNA replication
and repair. The replacement histone H3.3 is assembled by the histone
regulator A (HIRA; 600237) complex independently of DNA synthesis.
BIOCHEMICAL FEATURES
- Crystal Structure
Elsasser et al. (2012) reported the crystal structures of the DAXX
(603186) histone-binding domain with a histone H3.3-H4 (see 602822)
dimer, including mutants within DAXX and H3.3, together with in vitro
and in vivo functional studies that elucidated the principles underlying
H3.3 recognition specificity. Occupying 40% of the histone
surface-accessible area, DAXX wraps around the H3.3-H4 dimer, with
complex formation accompanied by structural transitions in the H3.3-H4
histone fold. DAXX uses an extended alpha-helical conformation to
compete with major interhistone, DNA, and ASF1 interaction sites.
Elsasser et al. (2012) concluded that their structural studies
identified recognition elements that read out H3.3-specific residues,
and functional studies addressed the contribution of gly90 in H3.3 and
glu225 in DAXX to chaperone-mediated H3.3 variant recognition
specificity.
MOLECULAR GENETICS
Schwartzentruber et al. (2012) sequenced the exomes of 48 pediatric
glioblastoma (137800) samples. Somatic mutations in the H3.3-ATRX
(300032)-DAXX (603186) chromatin remodeling pathway were identified in
44% of tumors (21 of 48). Recurrent mutations in H3F3A, which encodes
the replication-independent histone-3 variant H3.3, were observed in 31%
of tumors, and led to amino acid substitutions at 2 critical positions
within the histone tail (K27M, G34R/G34V) involved in key regulatory
posttranslational modifications. Mutations in ATRX and DAXX, encoding 2
subunits of a chromatin remodeling complex required for H3.3
incorporation at pericentric heterochromatin and telomeres, were
identified in 31% of samples overall, and in 100% of tumors harboring a
G34R or G34V H3.3 mutation. Somatic TP53 (191170) mutations were
identified in 54% of all cases, and in 86% of samples with H3F3A and/or
ATRX mutations. Screening of a large cohort of gliomas of various grades
and histologies (n = 784) showed H3F3A mutations to be specific to
glioblastoma multiforme and highly prevalent in children and young
adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was
strongly associated with alternative lengthening of telomeres and
specific gene expression profiles. Schwartzentruber et al. (2012) stated
that this was the first report to highlight recurrent mutations in a
regulatory histone in humans, and that their data suggested that defects
of the chromatin architecture underlie pediatric and young adult
glioblastoma multiforme pathogenesis.
Wu et al. (2012) reported that a K27M mutation occurring in either H3F3A
or HIST1H3B (602819) was observed in 78% of diffuse intrinsic pontine
gliomas (DIPGs) and 22% of non-brain-stem gliomas.
Lewis et al. (2013) reported that human DIPGs containing the K27M
mutation in either histone H3.3 (H3F3A) or H3.1 (HIST1H3B) display
significantly lower overall amounts of H3 with trimethylated lysine-27
(H3K27me3) and that histone H3K27M transgenes are sufficient to reduce
the amounts of H3K27me3 in vitro and in vivo. Lewis et al. (2013) found
that H3K27M inhibits the enzymatic activity of the Polycomb repressive
complex-2 (PRC2) through interaction with the EZH2 (601573) subunit. In
addition, transgenes containing lysine-to-methionine substitutions at
other known methylated lysines (H3K9 and H3K36) are sufficient to cause
specific reduction in methylation through inhibition of SET domain
enzymes. Lewis et al. (2013) proposed that K-to-M substitutions may
represent a mechanism to alter epigenetic states in a variety of
pathologies.
Behjati et al. (2013) reported exquisite tumor type specificity for
different histone H3.3 driver alterations. In 73 of 77 cases (95%) of
chondroblastoma, Behjati et al. (2013) found K36M alterations
predominantly encoded by H3F3B (601058), which is 1 of 2 genes for
histone H3.3. In contrast, in 92% (49 of 53) of giant cell tumors of
bone, Behjati et al. (2013) found histone H3.3 alterations exclusively
in H3F3A, leading to G34W or, in 1 case, G34L alterations. The mutations
were restricted to the stromal cell population and were not detected in
osteoclasts or their precursors. In the context of previously reported
H3F3A mutations encoding K27M and G34R or G34V alterations in childhood
brain tumors, a picture of tumor type specificity for histone H3.3
driver alterations emerged, indicating that histone H3.3 residues,
mutations, and genes have distinct functions.
*FIELD* RF
1. Albig, W.; Bramlage, B.; Gruber, K.; Klobeck, H.-G.; Kunz, J.;
Doenecke, D.: The human replacement histone H3.3B gene (H3F3B). Genomics 30:
264-272, 1995.
2. Behjati, S.; Tarpey, P. S.; Presneau, N.; Scheipl, S.; Pillay,
N.; Van Loo, P.; Wedge, D. C.; Cooke, S. L.; Gundem, G.; Davies, H.;
Nik-Zainal, S.; Martin, S.; and 17 others: Distinct H3F3A and H3F3B
driver mutations define chondroblastoma and giant cell tumor of bone. Nature
Genet. 45 1479-1482, 2013.
3. Chalmers, M.; Wells, D.: Extreme sequence conservation characterizes
the rabbit H3.3A histone cDNA. Nucleic Acids Res. 18: 3075, 1990.
4. Elsasser, S. J.; Huang, H.; Lewis, P. W.; Chin, J. W.; Allis, C.
D.; Patel, D. J.: DAXX envelops a histone H3.3-H4 dimer for H3.3-specific
recognition. Nature 491: 560-565, 2012.
5. Frank, D.; Doenecke, D.; Albig, W.: Differential expression of
human replacement and cell cycle dependent H3 histone genes. Gene 312:
135-143, 2003.
6. Hake, S. B.; Garcia, B. A.; Duncan, E. M.; Kauer, M.; Dellaire,
G.; Shabanowitz, J.; Bazett-Jones, D. P.; Allis, C. D.; Hunt, D. F.
: Expression patterns and post-translational modifications associated
with mammalian histone H3 variants. J. Biol. Chem. 281: 559-568,
2006.
7. Jin, C.; Zang, C.; Wei, G.; Cui, K.; Peng, W.; Zhao, K.; Felsenfeld,
G.: H3.3/H2A.Z double variant-containing nucleosomes mark 'nucleosome-free
regions' of active promoters and other regulatory regions. Nature
Genet. 41: 941-945, 2009.
8. Lewis, P. W.; Muller, M. M.; Koletsky, M. S.; Cordero, F.; Lin,
S.; Banaszynski, L. A.; Garcia, B. A.; Muir, T. W.; Becher, O. J.;
Allis, C. D.: Inhibition of PRC2 activity by a gain-of-function H3
mutation found in pediatric glioblastoma. Science 340: 857-861,
2013.
9. Lin, X.; Wells, D. E.: Localization of the human H3F3A histone
gene to 1q41, outside of the normal histone gene clusters. Genomics 46:
526-528, 1997.
10. Schwartzentruber, J.; Korshunov, A; Liu, X.-Y.; Jones, D. T. W.;
Pfaff, E.; Jacob, K.; Sturm, D.; Fontebasso, A. M.; Quang, D.-A. K.;
Tonjes, M.; Hovestadt, V.; Albrecht, S.; and 50 others: Driver
mutations in histone H3.3 and chromatin remodelling genes in paediatric
glioblastoma. Nature 482: 226-231, 2012. Note: Erratum: Nature 484:
130 only, 2012.
11. Talbert, P. B.; Henikoff, S.: Histone variants--ancient wrap
artists of the epigenome. Nature Rev. Molec. Cell Biol. 11: 264-275,
2010.
12. Wells, D.; Hoffman, D.; Kedes, L.: Unusual structure, evolutionary
conservation of non-coding sequences and numerous pseudogenes characterize
the H3.3 histone multigene family. Nucleic Acids Res. 15: 2871-2889,
1987.
13. Wells, D.; Kedes, L.: Structure of a human histone cDNA: evidence
that basally expressed histone genes have intervening sequences and
encode polyadenylated mRNAs. Proc. Nat. Acad. Sci. 82: 2834-2838,
1985.
14. Witt, O.; Albig, W.; Doenecke, D.: Transcriptional regulation
of the human replacement histone gene H3.3B. FEBS Lett. 408: 255-260,
1997.
15. Wu, G.; Broniscer, A.; McEachron, T. A.; Lu, C.; Paugh, B. S.;
Becksfort, J.; Qu, C.; Ding, L.; Huether, R.; Parker, M.; Zhang, J.;
Gajjar, A.; and 9 others: Somatic histone H3 alterations in pediatric
diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nature
Genet 44: 251-253, 2012.
16. Xu, M.; Long, C.; Chen, X.; Huang, C.; Chen, S.; Zhu, B.: Partitioning
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*FIELD* CN
Ada Hamosh - updated: 01/14/2014
Ada Hamosh - updated: 6/24/2013
Patricia A. Hartz - updated: 2/6/2013
Matthew B. Gross - updated: 2/4/2013
Ada Hamosh - updated: 12/13/2012
Ada Hamosh - updated: 9/6/2012
Ada Hamosh - updated: 8/29/2012
Ada Hamosh - updated: 3/7/2012
Patricia A. Hartz - updated: 5/14/2010
Patricia A. Hartz - updated: 5/12/2010
Ada Hamosh - updated: 4/28/2010
Ada Hamosh - updated: 4/13/2010
Ada Hamosh - updated: 3/11/2010
Ada Hamosh - updated: 2/1/2010
Ada Hamosh - updated: 10/19/2009
Ada Hamosh - updated: 9/16/2009
Ada Hamosh - updated: 9/9/2009
Ada Hamosh - updated: 8/10/2009
Cassandra L. Kniffin - updated: 6/8/2009
Ada Hamosh - updated: 6/4/2009
Ada Hamosh - updated: 5/23/2008
Ada Hamosh - updated: 3/26/2008
Ada Hamosh - updated: 3/6/2008
Ada Hamosh - updated: 2/21/2008
Ada Hamosh - updated: 11/26/2007
Ada Hamosh - updated: 8/28/2007
Ada Hamosh - updated: 8/13/2007
Ada Hamosh - updated: 8/15/2006
George E. Tiller - updated: 1/31/2006
Ada Hamosh - updated: 1/12/2006
Ada Hamosh - updated: 11/3/2005
Ada Hamosh - updated: 10/25/2005
Ada Hamosh - updated: 8/18/2005
Ada Hamosh - updated: 12/15/2004
Ada Hamosh - updated: 6/17/2003
Ada Hamosh - updated: 4/15/2003
Ada Hamosh - updated: 11/20/2002
Stylianos E. Antonarakis - updated: 1/7/2002
Ada Hamosh - updated: 8/14/2001
Ada Hamosh - updated: 8/5/1999
Rebekah S. Rasooly - updated: 7/8/1998
*FIELD* CD
Alan F. Scott: 3/18/1996
*FIELD* ED
alopez: 01/14/2014
alopez: 6/24/2013
mgross: 2/8/2013
mgross: 2/6/2013
mgross: 2/4/2013
alopez: 12/21/2012
terry: 12/13/2012
alopez: 9/7/2012
terry: 9/6/2012
alopez: 9/4/2012
terry: 8/29/2012
terry: 5/22/2012
mgross: 5/3/2012
terry: 5/1/2012
carol: 4/11/2012
alopez: 3/12/2012
terry: 3/7/2012
terry: 4/20/2011
carol: 7/29/2010
mgross: 5/17/2010
terry: 5/14/2010
terry: 5/12/2010
alopez: 4/29/2010
terry: 4/28/2010
alopez: 4/14/2010
terry: 4/13/2010
carol: 4/5/2010
alopez: 3/11/2010
alopez: 2/1/2010
alopez: 1/27/2010
terry: 1/15/2010
alopez: 11/9/2009
alopez: 10/26/2009
terry: 10/19/2009
alopez: 9/22/2009
terry: 9/16/2009
terry: 9/9/2009
alopez: 8/19/2009
mgross: 8/10/2009
terry: 8/10/2009
wwang: 6/17/2009
ckniffin: 6/8/2009
alopez: 6/4/2009
joanna: 6/2/2009
terry: 5/19/2009
alopez: 6/2/2008
terry: 5/23/2008
alopez: 3/26/2008
alopez: 3/25/2008
terry: 3/6/2008
carol: 2/29/2008
terry: 2/21/2008
alopez: 11/29/2007
terry: 11/26/2007
alopez: 9/7/2007
terry: 8/28/2007
carol: 8/15/2007
terry: 8/13/2007
carol: 8/15/2006
wwang: 1/31/2006
alopez: 1/13/2006
terry: 1/12/2006
alopez: 11/7/2005
terry: 11/3/2005
alopez: 10/26/2005
terry: 10/25/2005
alopez: 8/23/2005
terry: 8/18/2005
alopez: 12/15/2004
alopez: 6/19/2003
terry: 6/17/2003
alopez: 4/17/2003
terry: 4/15/2003
cwells: 11/20/2002
terry: 11/18/2002
mgross: 1/7/2002
alopez: 8/20/2001
terry: 8/14/2001
alopez: 8/5/1999
alopez: 8/26/1998
alopez: 7/8/1998
mark: 9/22/1996
terry: 3/26/1996
mark: 3/19/1996
mark: 3/18/1996