[1]	NUCLEOTIDE SEQUENCE [MRNA]. STRAIN=129/Sv; DOI=10.1093/nar/19.9.2441; PubMed=2041781 [NCBI, ExPASy, EBI, Israel, Japan] Nagata T., Kato T., Morita T., Nozaki M., Kubota H., Yagi H., Matsushiro A.; "Polyadenylated and 3' processed mRNAs are transcribed from the mouse histone H2A.X gene."; Nucleic Acids Res. 19:2441-2447(1991).
[2]	NUCLEOTIDE SEQUENCE [GENOMIC DNA]. STRAIN=C3H; TISSUE=Placenta; DOI=10.1016/0888-7543(95)80145-C; PubMed=7774939 [NCBI, ExPASy, EBI, Israel, Japan] Porcher C., Grandchamp B.; "Structure of the mouse H2A.X gene and physical linkage to the UPS locus on chromosome 9: assignment of the human H2A.X gene to 11q23 by sequence analysis."; Genomics 25:312-313(1995).
[3]	NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. STRAIN=C57BL/6J; TISSUE=Mammary gland; DOI=10.1101/gr.2596504; PubMed=15489334 [NCBI, ExPASy, EBI, Israel, Japan] The MGC Project Team; "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."; Genome Res. 14:2121-2127(2004).
[4]	UBIQUITINATION. DOI=10.1021/bi00555a022; PubMed=7407044 [NCBI, ExPASy, EBI, Israel, Japan] West M.H.P., Bonner W.M.; "Histone 2A, a heteromorphous family of eight protein species."; Biochemistry 19:3238-3245(1980).
[5]	PHOSPHORYLATION AT SER-2, AND ACETYLATION AT SER-2. PubMed=7217105 [NCBI, ExPASy, EBI, Israel, Japan] Pantazis P., Bonner W.M.; "Quantitative determination of histone modification. H2A acetylation and phosphorylation."; J. Biol. Chem. 256:4669-4675(1981).
[6]	PHOSPHORYLATION AT SER-140. DOI=10.1074/jbc.273.10.5858; PubMed=9488723 [NCBI, ExPASy, EBI, Israel, Japan] Rogakou E.P., Pilch D.R., Orr A.H., Ivanova V.S., Bonner W.M.; "DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139."; J. Biol. Chem. 273:5858-5868(1998).
[7]	SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140. DOI=10.1074/jbc.C100466200; PubMed=11571274 [NCBI, ExPASy, EBI, Israel, Japan] Burma S., Chen B.P., Murphy M., Kurimasa A., Chen D.J.; "ATM phosphorylates histone H2AX in response to DNA double-strand breaks."; J. Biol. Chem. 276:42462-42467(2001).
[8]	FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140. DOI=10.1038/414660a; PubMed=11740565 [NCBI, ExPASy, EBI, Israel, Japan] Petersen S., Casellas R., Reina-San-Martin B., Chen H.T., Difilippantonio M.J., Wilson P.C., Hanitsch L., Celeste A., Muramatsu M., Pilch D.R., Redon C., Ried T., Bonner W.M., Honjo T., Nussenzweig M.C., Nussenzweig A.; "AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching."; Nature 414:660-665(2001).
[9]	SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-140, AND TISSUE SPECIFICITY. DOI=10.1038/85830; PubMed=11242108 [NCBI, ExPASy, EBI, Israel, Japan] Mahadevaiah S.K., Turner J.M.A., Baudat F., Rogakou E.P., de Boer P., Blanco-Rodriguez J., Jasin M., Keeney S., Bonner W.M., Burgoyne P.S.; "Recombinational DNA double-strand breaks in mice precede synapsis."; Nat. Genet. 27:271-276(2001).
[10]	FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140. DOI=10.1038/ncb884; PubMed=12447390 [NCBI, ExPASy, EBI, Israel, Japan] Fernandez-Capetillo O., Chen H.-T., Celeste A., Ward I., Romanienko P.J., Morales J.C., Naka K., Xia Z., Camerini-Otero R.D., Motoyama N., Carpenter P.B., Bonner W.M., Chen J., Nussenzweig A.; "DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1."; Nat. Cell Biol. 4:993-997(2002).
[11]	FUNCTION, AND SUBCELLULAR LOCATION. DOI=10.1073/pnas.122228699; PubMed=12034884 [NCBI, ExPASy, EBI, Israel, Japan] Bassing C.H., Chua K.F., Sekiguchi J., Suh H., Whitlow S.R., Fleming J.C., Monroe B.C., Ciccone D.N., Yan C., Vlasakova K., Livingston D.M., Ferguson D.O., Scully R., Alt F.W.; "Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX."; Proc. Natl. Acad. Sci. U.S.A. 99:8173-8178(2002).
[12]	FUNCTION. DOI=10.1126/science.1069398; PubMed=11934988 [NCBI, ExPASy, EBI, Israel, Japan] Celeste A., Petersen S., Romanienko P.J., Fernandez-Capetillo O., Chen H.T., Sedelnikova O.A., Reina-San-Martin B., Coppola V., Meffre E., Difilippantonio M.J., Redon C., Pilch D.R., Olaru A., Eckhaus M., Camerini-Otero R.D., Tessarollo L., Livak F., Manova K., Bonner W.M., Nussenzweig M.C., Nussenzweig A.; "Genomic instability in mice lacking histone H2AX."; Science 296:922-927(2002).
[13]	FUNCTION. DOI=10.1016/S0092-8674(03)00566-X; PubMed=12914700 [NCBI, ExPASy, EBI, Israel, Japan] Bassing C.H., Suh H., Ferguson D.O., Chua K.F., Manis J., Eckersdorff M., Gleason M., Bronson R., Lee C., Alt F.W.; "Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors."; Cell 114:359-370(2003).
[14]	FUNCTION, AND MUTAGENESIS OF SER-137 AND SER-140. DOI=10.1016/S0092-8674(03)00567-1; PubMed=12914701 [NCBI, ExPASy, EBI, Israel, Japan] Celeste A., Difilippantonio S., Difilippantonio M.J., Fernandez-Capetillo O., Pilch D.R., Sedelnikova O.A., Eckhaus M., Ried T., Bonner W.M., Nussenzweig A.; "H2AX haploinsufficiency modifies genomic stability and tumor susceptibility."; Cell 114:371-383(2003).
[15]	FUNCTION. DOI=10.1016/S1534-5807(03)00093-5; PubMed=12689589 [NCBI, ExPASy, EBI, Israel, Japan] Fernandez-Capetillo O., Mahadevaiah S.K., Celeste A., Romanienko P.J., Camerini-Otero R.D., Bonner W.M., Manova K., Burgoyne P., Nussenzweig A.; "H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis."; Dev. Cell 4:497-508(2003).
[16]	INTERACTION WITH TP53BP1. DOI=10.1074/jbc.C300117200; PubMed=12697768 [NCBI, ExPASy, EBI, Israel, Japan] Ward I.M., Minn K., Jorda K.G., Chen J.; "Accumulation of checkpoint protein 53BP1 at DNA breaks involves its binding to phosphorylated histone H2AX."; J. Biol. Chem. 278:19579-19582(2003).
[17]	FUNCTION, AND PHOSPHORYLATION AT SER-140. DOI=10.1074/jbc.M300198200; PubMed=12660252 [NCBI, ExPASy, EBI, Israel, Japan] Furuta T., Takemura H., Liao Z.-Y., Aune G.J., Redon C., Sedelnikova O.A., Pilch D.R., Rogakou E.P., Celeste A., Chen H.T., Nussenzweig A., Aladjem M.I., Bonner W.M., Pommier Y.; "Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes."; J. Biol. Chem. 278:20303-20312(2003).
[18]	FUNCTION, AND PHOSPHORYLATION AT SER-140. DOI=10.1083/jcb.200305124; PubMed=14530383 [NCBI, ExPASy, EBI, Israel, Japan] Fernandez-Capetillo O., Liebe B., Scherthan H., Nussenzweig A.; "H2AX regulates meiotic telomere clustering."; J. Cell Biol. 163:15-20(2003).
[19]	FUNCTION. DOI=10.1038/ncb1004; PubMed=12792649 [NCBI, ExPASy, EBI, Israel, Japan] Celeste A., Fernandez-Capetillo O., Kruhlak M.J., Pilch D.R., Staudt D.W., Lee A., Bonner R.F., Bonner W.M., Nussenzweig A.; "Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks."; Nat. Cell Biol. 5:675-679(2003).
[20]	SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140. DOI=10.1158/0008-5472.CAN-03-3207; PubMed=15059890 [NCBI, ExPASy, EBI, Israel, Japan] Stiff T., O'Driscoll M., Rief N., Iwabuchi K., Loebrich M., Jeggo P.A.; "ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation."; Cancer Res. 64:2390-2396(2004).
[21]	FUNCTION, AND SUBCELLULAR LOCATION. DOI=10.1016/j.cub.2004.11.032; PubMed=15589157 [NCBI, ExPASy, EBI, Israel, Japan] Turner J.M.A., Aprelikova O., Xu X., Wang R., Kim S., Chandramouli G.V.R., Barrett J.C., Burgoyne P.S., Deng C.-X.; "BRCA1, histone H2AX phosphorylation, and male meiotic sex chromosome inactivation."; Curr. Biol. 14:2135-2142(2004).
[22]	FUNCTION. DOI=10.1016/j.molcel.2004.10.029; PubMed=15574327 [NCBI, ExPASy, EBI, Israel, Japan] Riballo E., Kuehne M., Rief N., Doherty A., Smith G.C.M., Recio M.-J., Reis C., Dahm K., Fricke A., Krempler A., Parker A.R., Jackson S.P., Gennery A., Jeggo P.A., Loebrich M.; "A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci."; Mol. Cell 16:715-724(2004).
[23]	FUNCTION, AND MUTAGENESIS OF SER-140. DOI=10.1016/j.molcel.2004.12.007; PubMed=15610743 [NCBI, ExPASy, EBI, Israel, Japan] Xie A., Puget N., Shim I., Odate S., Jarzyna I., Bassing C.H., Alt F.W., Scully R.; "Control of sister chromatid recombination by histone H2AX."; Mol. Cell 16:1017-1025(2004).
[24]	FUNCTION. DOI=10.1128/MCB.25.2.661-670.2005; PubMed=15632067 [NCBI, ExPASy, EBI, Israel, Japan] Kang J., Ferguson D., Song H., Bassing C., Eckersdorff M., Alt F.W., Xu Y.; "Functional interaction of H2AX, NBS1, and p53 in ATM-dependent DNA damage responses and tumor suppression."; Mol. Cell. Biol. 25:661-670(2005).
[25]	FUNCTION, AND PHOSPHORYLATION AT SER-140. DOI=10.1038/ng1484; PubMed=15580272 [NCBI, ExPASy, EBI, Israel, Japan] Turner J.M.A., Mahadevaiah S.K., Fernandez-Capetillo O., Nussenzweig A., Xu X., Deng C.-X., Burgoyne P.S.; "Silencing of unsynapsed meiotic chromosomes in the mouse."; Nat. Genet. 37:41-47(2005).
[26]	PHOSPHORYLATION AT TYR-143. DOI=10.1038/nature07668; PubMed=19092802 [NCBI, ExPASy, EBI, Israel, Japan] Xiao A., Li H., Shechter D., Ahn S.H., Fabrizio L.A., Erdjument-Bromage H., Ishibe-Murakami S., Wang B., Tempst P., Hofmann K., Patel D.J., Elledge S.J., Allis C.D.; "WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity."; Nature 457:57-62(2009).

Comments

FUNCTION: Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. Required for checkpoint-mediated arrest of cell cycle progression in response to low doses of ionizing radiation and for efficient repair of DNA double strand breaks (DSBs) specifically when modified by C-terminal phosphorylation.
SUBUNIT: The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. May interact with numerous proteins required for DNA damage signaling and repair when phosphorylated on Ser-140. These include MDC1, TP53BP1 and the MRN complex, composed of MRE11A, RAD50, and NBN. Interaction with the MRN complex is likely mediated at least in part by NBN. May also interact with DHX9/NDHII when phosphorylated on Ser-140.
SUBCELLULAR LOCATION: Nucleus.
TISSUE SPECIFICITY: Most abundant in testis, thymus and spleen.
DEVELOPMENTAL STAGE: Synthesized in G1 as well as in S-phase.
DOMAIN: The [ST]-Q motif constitutes a recognition sequence for kinases from the PI3/PI4-kinase family.
PTM: Phosphorylated on Ser-140 (to form gamma-H2AFX or H2AX139ph) in response to DNA double strand breaks (DSBs) generated by exogenous genotoxic agents, by stalled replication forks, by meiotic recombination events and during immunoglobulin class switching in lymphocytes. Phosphorylation can extend up to several thousand nucleosomes from the actual site of the DSB and may mark the surrounding chromatin for recruitment of proteins required for DNA damage signaling and repair. Widespread phosphorylation may also serve to amplify the damage signal or aid repair of persistent lesions. Phosphorylation of Ser-140 (H2AX139ph) in response to ionizing radiation is mediated by both ATM and PRKDC while defects in DNA replication induce Ser-140 phosphorylation (H2AX139ph) subsequent to activation of ATR and PRKDC. Dephosphorylation of Ser-140 by PP2A is required for DNA DSB repair. In meiosis, Ser-140 phosphorylation (H2AX139ph) first occurs at synaptonemal complexes during leptotene and is an ATM-dependent response to the formation of programmed DSBs by SPO11. Ser-140 phosphorylation (H2AX139ph) subsequently occurs at unsynapsed regions of both autosomes and the XY bivalent during zygotene and is ATR- and BRCA1-dependent. Ser-140 phosphorylation (H2AX139ph) may also be required for transcriptional repression of unsynapsed chromatin and meiotic sex chromosome inactivation (MSCI), whereby the X and Y chromosomes condense in pachytene to form the heterochromatic XY-body. During immunoglobulin class switch recombination in lymphocytes, Ser-140 phosphorylation (H2AX139ph) at sites of DNA-recombination requires the activation-induced cytidine deaminase AICDA. Phosphorylation at Tyr-143 (H2AXY142ph) by BAZ1B/WSTF determines the relative recruitment of either DNA repair or pro-apoptotic factors. Phosphorylation at Tyr-143 (H2AXY142ph) favors the recruitment of APBB1/FE65 and pro-apoptosis factors such as MAPK8/JNK1, triggering apoptosis. In contrast, dephosphorylation of Tyr-143 by EYA proteins (EYA1, EYA2, EYA3 or EYA4) favors the recruitment of MDC1-containing DNA repair complexes to the tail of phosphorylated Ser-140 (H2AX139ph).
PTM: Monoubiquitination of Lys-120 (H2AXK119ub) by RING1 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression (Probable). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Monoubiquitination and ionizing radiation-induced 'Lys-63'-linked ubiquitination are distinct events (By similarity).
MISCELLANEOUS: Haploinsufficient for the suppression of genomic instability. This phenotype is further exacerbated in the absence of TP53.
SIMILARITY: Belongs to the histone H2A family.

Copyright

Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms. Distributed under the Creative Commons Attribution-NoDerivs License.

Cross-references

Sequence databases

EMBL

X58069; CAA41099.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
Z35401; CAA84585.1; -; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
BC005468; AAH05468.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
BC010336; AAH10336.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]

IPI00230264; -.

I48406; I48406.

NP_034566.1; -.

3D structure databases

HSSP

P06897; 1AOI. [HSSP ENTRY / PDB]

SMR

P27661; 2-123.

ModBase

P27661.

Protein-protein interaction databases

IntAct

P27661; 1.

PTM databases

PhosphoSite

P27661; -.

Organism-specific databases

MGI

MGI:102688; H2afx.

Gene expression databases

P27661; -.

P27661; -.

MM_H2AFX; -.

ENSMUSG00000049932; Mus musculus.

Ontologies

GO:0001673;	Cellular component: male germ cell nucleus (inferred from direct assay from MGI).
GO:0000786;	Cellular component: nucleosome (inferred from electronic annotation from UniProtKB-KW).
GO:0005657;	Cellular component: replication fork (inferred from direct assay from MGI).
GO:0001741;	Cellular component: XY body (inferred from direct assay from MGI).
GO:0003684;	Molecular function: damaged DNA binding (inferred from direct assay from MGI).
GO:0005515;	Molecular function: protein binding (inferred from physical interaction from UniProtKB).
GO:0000724;	Biological process: double-strand break repair via homologous recombination (inferred from mutant phenotype from MGI).
GO:0007126;	Biological process: meiosis (inferred from electronic annotation from UniProtKB-KW).
GO:0006334;	Biological process: nucleosome assembly (inferred from electronic annotation from InterPro).
GO:0007283;	Biological process: spermatogenesis (inferred from mutant phenotype from MGI).
QuickGo view.

Family and domain databases

InterPro

IPR007125; Histone_core_D.
IPR002119; Histone_H2A.
Graphical view of domain structure.

PANTHER

PTHR23430; Histone_H2A; 1.

Pfam

PF00125; Histone; 1.
Pfam graphical view of domain structure.

PRINTS

PR00620; HISTONEH2A.

ProDom

PD000522; Histone_H2A; 1.
[Domain structure / List of seq. sharing at least 1 domain]

SMART

SM00414; H2A; 1.
SMART graphical view of domain structure.

PROSITE

PS00046; HISTONE_H2A; 1.

Proteomic databases

PRIDE

P27661; -.

Genome annotation databases

Ensembl

ENSMUSG00000049932; Mus musculus. [Contig view]

GeneID

15270; -.

KEGG

mmu:15270; -.

Phylogenomic databases

HOVERGEN

P27661; -.

OMA

P27661; SQASQEY.

Other

287897; -.

H2afx; Mus musculus.

View cluster of proteins with at least 50% / 90% / 100% identity.

Keywords

Acetylation; Cell cycle; Chromosomal protein; DNA damage; DNA recombination; DNA repair; DNA-binding; Isopeptide bond; Meiosis; Nucleosome core; Nucleus; Phosphoprotein; Ubl conjugation.

Features

Feature table viewer

`Key`	`From To`	`Length`	`Description`	`FTId`
`INIT_MET`	`1 1`		`Removed (By similarity).`
`CHAIN`	`2 143`	`142`	`Histone H2A.x.`	`PRO_0000055243`
`MOTIF`	`140 141`	`2`	`[ST]-Q motif.`
`MOD_RES`	`2 2`		`N-acetylserine.`
`MOD_RES`	`2 2`		`Phosphoserine.`
`MOD_RES`	`140 140`		`Phosphoserine; by ATM, ATR and PRKDC.`
`MOD_RES`	`143 143`		`Phosphotyrosine; by WSTF.`
`CROSSLNK`	`120 120`		`Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) (Probable).`
`MUTAGEN`	`137 137`		`S->A: Increased genomic instability and radiation sensitivity; when associated with A-140.`
`MUTAGEN`	`140 140`		`S->A: Increased genomic instability and radiation sensitivity; when associated with A-137. Reduced homologous recombination.`

Sequence information

Length: 143 AA [This is the length of the unprocessed precursor]

Molecular weight: 15143 Da [This is the MW of the unprocessed precursor]

CRC64: A3683760C13CC2B9 [This is a checksum on the sequence]

        10         20         30         40         50         60 
MSGRGKTGGK ARAKAKSRSS RAGLQFPVGR VHRLLRKGHY AERVGAGAPV YLAAVLEYLT 

        70         80         90        100        110        120 
AEILELAGNA ARDNKKTRII PRHLQLAIRN DEELNKLLGG VTIAQGGVLP NIQAVLLPKK 

       130        140 
SSATVGPKAP AVGKKASQAS QEY

P27661 in FASTA format

View entry in raw text format (no links)
Report form for errors/updates in this UniProtKB/Swiss-Prot entry

	BLAST submission on ExPASy/SIB or at NCBI (USA)		Sequence analysis tools: ProtParam, ProtScale, Compute pI/Mw, PeptideMass, PeptideCutter, Dotlet (Java)
	ScanProsite, MotifScan		Submit a homology modeling request to SWISS-MODEL
	NPSA Sequence analysis tools