Reviewed,
UniProtKB/Swiss-Prot P27661 (H2AX_MOUSE)
Last modified
June 16, 2009.
Version 91.
History...
Clusters with 100%,
90%,
50% identity |
Documents (2) |
Third-party data |
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Names and origin
| Protein names | Recommended name: Histone H2A.x Short name=H2a/x | ||||
| Gene names |
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| Organism | Mus musculus (Mouse) | ||||
| Taxonomic identifier | 10090 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus |
Protein attributes
| Sequence length | 143 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is further processed into a mature form. |
| Protein existence | Evidence at protein level. |
General annotation (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. Ref.8 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.17 Ref.18 Ref.19 Ref.21 Ref.22 Ref.23 Ref.24 Ref.25 |
| Subunit structure | 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 | |
| Tissue specificity | Most abundant in testis, thymus and spleen. Ref.9 |
| 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. |
| Post-translational modification | 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). 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. |
| Sequence similarities | Belongs to the histone H2A family. |
Ontologies
| Keywords | |
|---|---|
| Biological process | Cell cycle DNA damage DNA recombination DNA repair Meiosis |
| Cellular component | Chromosomal protein Nucleosome core Nucleus |
| Ligand | DNA-binding |
| PTM | Acetylation Isopeptide bond Phosphoprotein Ubl conjugation |
| Gene Ontology (GO) | |
| Biological process | double-strand break repair via homologous recombination Ref.12 Inferred from mutant phenotype. Source: MGI meiosisInferred from electronic annotation. Source: UniProtKB-KW nucleosome assemblyInferred from electronic annotation. Source: InterPro spermatogenesis Ref.12Inferred from mutant phenotype. Source: MGI |
| Cellular component | XY body Inferred from direct assay. Source: MGI male germ cell nucleusInferred from direct assay. Source: MGI nucleosomeInferred from electronic annotation. Source: UniProtKB-KW replication forkInferred from direct assay. Source: MGI |
| Molecular function | damaged DNA binding Ref.12 Inferred from direct assay. Source: MGI protein binding Ref.26Inferred from physical interaction. Source: UniProtKB |
| Complete GO annotation... | |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||
Molecule processing | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Initiator methionine | 1 | 1 | Removed By similarity | ||||||
| Chain | 2 – 143 | 142 | Histone H2A.x | PRO_0000055243 | |||||
Regions | |||||||||
| Motif | 140 – 141 | 2 | [ST]-Q motif | ||||||
Amino acid modifications | |||||||||
| Modified residue | 2 | 1 | N-acetylserine Ref.5 | ||||||
| Modified residue | 2 | 1 | Phosphoserine Ref.5 | ||||||
| Modified residue | 140 | 1 | Phosphoserine; by ATM, ATR and PRKDC Ref.8 Ref.10 Ref.17 Ref.18 Ref.25 Ref.7 Ref.9 Ref.20 Ref.6 | ||||||
| Modified residue | 143 | 1 | Phosphotyrosine; by WSTF | ||||||
| Cross-link | 120 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Probable | |||||||
Experimental info | |||||||||
| Mutagenesis | 137 | 1 | S → A: Increased genomic instability and radiation sensitivity; when associated with A-140. Ref.14 | ||||||
| Mutagenesis | 140 | 1 | S → A: Increased genomic instability and radiation sensitivity; when associated with A-137. Reduced homologous recombination. Ref.14 Ref.23 | ||||||
Sequences
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References
| « Hide 'large scale' references | |
| [1] | "Polyadenylated and 3' processed mRNAs are transcribed from the mouse histone H2A.X gene." Nagata T., Kato T., Morita T., Nozaki M., Kubota H., Yagi H., Matsushiro A. Nucleic Acids Res. 19:2441-2447(1991) [PubMed: 2041781] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: 129/Sv. |
| [2] | "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." Porcher C., Grandchamp B. Genomics 25:312-313(1995) [PubMed: 7774939] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: C3H. Tissue: Placenta. |
| [3] | "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J. Tissue: Mammary gland. |
| [4] | "Histone 2A, a heteromorphous family of eight protein species." West M.H.P., Bonner W.M. Biochemistry 19:3238-3245(1980) [PubMed: 7407044] [Abstract] Cited for: UBIQUITINATION. |
| [5] | "Quantitative determination of histone modification. H2A acetylation and phosphorylation." Pantazis P., Bonner W.M. J. Biol. Chem. 256:4669-4675(1981) [PubMed: 7217105] [Abstract] Cited for: PHOSPHORYLATION AT SER-2, ACETYLATION AT SER-2. |
| [6] | "DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139." Rogakou E.P., Pilch D.R., Orr A.H., Ivanova V.S., Bonner W.M. J. Biol. Chem. 273:5858-5868(1998) [PubMed: 9488723] [Abstract] Cited for: PHOSPHORYLATION AT SER-140. |
| [7] | "ATM phosphorylates histone H2AX in response to DNA double-strand breaks." Burma S., Chen B.P., Murphy M., Kurimasa A., Chen D.J. J. Biol. Chem. 276:42462-42467(2001) [PubMed: 11571274] [Abstract] Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-140. |
| [8] | "AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching." 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. Nature 414:660-665(2001) [PubMed: 11740565] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-140. |
| [9] | "Recombinational DNA double-strand breaks in mice precede synapsis." 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. Nat. Genet. 27:271-276(2001) [PubMed: 11242108] [Abstract] Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-140, TISSUE SPECIFICITY. |
| [10] | "DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1." 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. Nat. Cell Biol. 4:993-997(2002) [PubMed: 12447390] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-140. |
| [11] | "Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX." 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. Proc. Natl. Acad. Sci. U.S.A. 99:8173-8178(2002) [PubMed: 12034884] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION. |
| [12] | "Genomic instability in mice lacking histone H2AX." 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. Nussenzweig A.Science 296:922-927(2002) [PubMed: 11934988] [Abstract] Cited for: FUNCTION. |
| [13] | "Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors." Bassing C.H., Suh H., Ferguson D.O., Chua K.F., Manis J., Eckersdorff M., Gleason M., Bronson R., Lee C., Alt F.W. Cell 114:359-370(2003) [PubMed: 12914700] [Abstract] Cited for: FUNCTION. |
| [14] | "H2AX haploinsufficiency modifies genomic stability and tumor susceptibility." 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. Cell 114:371-383(2003) [PubMed: 12914701] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF SER-137 AND SER-140. |
| [15] | "H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis." Fernandez-Capetillo O., Mahadevaiah S.K., Celeste A., Romanienko P.J., Camerini-Otero R.D., Bonner W.M., Manova K., Burgoyne P., Nussenzweig A. Dev. Cell 4:497-508(2003) [PubMed: 12689589] [Abstract] Cited for: FUNCTION. |
| [16] | "Accumulation of checkpoint protein 53BP1 at DNA breaks involves its binding to phosphorylated histone H2AX." Ward I.M., Minn K., Jorda K.G., Chen J. J. Biol. Chem. 278:19579-19582(2003) [PubMed: 12697768] [Abstract] Cited for: INTERACTION WITH TP53BP1. |
| [17] | "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." 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. J. Biol. Chem. 278:20303-20312(2003) [PubMed: 12660252] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-140. |
| [18] | "H2AX regulates meiotic telomere clustering." Fernandez-Capetillo O., Liebe B., Scherthan H., Nussenzweig A. J. Cell Biol. 163:15-20(2003) [PubMed: 14530383] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-140. |
| [19] | "Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks." Celeste A., Fernandez-Capetillo O., Kruhlak M.J., Pilch D.R., Staudt D.W., Lee A., Bonner R.F., Bonner W.M., Nussenzweig A. Nat. Cell Biol. 5:675-679(2003) [PubMed: 12792649] [Abstract] Cited for: FUNCTION. |
| [20] | "ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation." Stiff T., O'Driscoll M., Rief N., Iwabuchi K., Loebrich M., Jeggo P.A. Cancer Res. 64:2390-2396(2004) [PubMed: 15059890] [Abstract] Cited for: SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-140. |
| [21] | "BRCA1, histone H2AX phosphorylation, and male meiotic sex chromosome inactivation." 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. Curr. Biol. 14:2135-2142(2004) [PubMed: 15589157] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION. |
| [22] | "A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci." 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. Mol. Cell 16:715-724(2004) [PubMed: 15574327] [Abstract] Cited for: FUNCTION. |
| [23] | "Control of sister chromatid recombination by histone H2AX." Xie A., Puget N., Shim I., Odate S., Jarzyna I., Bassing C.H., Alt F.W., Scully R. Mol. Cell 16:1017-1025(2004) [PubMed: 15610743] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF SER-140. |
| [24] | "Functional interaction of H2AX, NBS1, and p53 in ATM-dependent DNA damage responses and tumor suppression." Kang J., Ferguson D., Song H., Bassing C., Eckersdorff M., Alt F.W., Xu Y. Mol. Cell. Biol. 25:661-670(2005) [PubMed: 15632067] [Abstract] Cited for: FUNCTION. |
| [25] | "Silencing of unsynapsed meiotic chromosomes in the mouse." Turner J.M.A., Mahadevaiah S.K., Fernandez-Capetillo O., Nussenzweig A., Xu X., Deng C.-X., Burgoyne P.S. Nat. Genet. 37:41-47(2005) [PubMed: 15580272] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-140. |
| [26] | "WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity." 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. Nature 457:57-62(2009) [PubMed: 19092802] [Abstract] Cited for: PHOSPHORYLATION AT TYR-143. |
| + | Additional computationally mapped references. |
Cross-references
Sequence databases | |
|---|---|
| X58069 mRNA. Translation: CAA41099.1. Z35401 Genomic DNA. Translation: CAA84585.1. BC005468 mRNA. Translation: AAH05468.1. BC010336 mRNA. Translation: AAH10336.1. | |
| IPI | IPI00230264. |
| PIR | I48406. |
| RefSeq | NP_034566.1. |
| UniGene | Mm.245931 |
3D structure databases | |
| HSSP | HSSP built from PDB template 1AOI based on UniProtKB P06897. |
| SMR | P27661. Positions 2-123. |
| ModBase | Search... |
Protein-protein interaction databases | |
| IntAct | P27661. 1 interaction. |
PTM databases | |
| PhosphoSite | P27661. |
Proteomic databases | |
| PRIDE | P27661. |
Genome annotation databases | |
| Ensembl | ENSMUSG00000049932. Mus musculus. [Contig view] |
| GeneID | 15270. |
| KEGG | mmu:15270. |
Organism-specific databases | |
| MGI | MGI:102688. H2afx. |
Phylogenomic databases | |
| HOVERGEN | P27661. |
| OMA | P27661. SQASQEY. |
Gene expression databases | |
| ArrayExpress | P27661. |
| Bgee | P27661. |
| CleanEx | MM_H2AFX. |
| GermOnline | ENSMUSG00000049932. Mus musculus. |
Family and domain databases | |
| InterPro | IPR007125. Histone_core_D. IPR002119. Histone_H2A. [Graphical view] |
| PANTHER | PTHR23430. Histone_H2A. 1 hit. |
| Pfam | PF00125. Histone. 1 hit. [Graphical view] |
| PRINTS | PR00620. HISTONEH2A. |
| ProDom | PD000522. Histone_H2A. 1 hit. [Graphical view] [Entries sharing at least one domain] |
| SMART | SM00414. H2A. 1 hit. [Graphical view] |
| PROSITE | PS00046. HISTONE_H2A. 1 hit. [Graphical view] |
| ProtoNet | Search... |
Other Resources | |
| NextBio | 287897. |
| SOURCE | Search... |
Entry information
| Entry name | H2AX_MOUSE | ||||||||
| Accession | Primary (citable) accession number: P27661 | ||||||||
| Entry history |
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| Entry status | Reviewed (UniProtKB/Swiss-Prot) | ||||||||
| Annotation project | HPI (Human Proteome Initiative) | ||||||||
Relevant documents
| MGD cross-references Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot |
| SIMILARITY comments Index of protein domains and families |

Clusters with


