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Protein

Histone H2AX

Gene

H2AFX

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.4 Publications

GO - Molecular functioni

  • damaged DNA binding Source: Ensembl
  • DNA binding Source: UniProtKB
  • enzyme binding Source: UniProtKB
  • histone binding Source: UniProtKB

GO - Biological processi

  • cellular response to DNA damage stimulus Source: BHF-UCL
  • cellular response to gamma radiation Source: Ensembl
  • cellular senescence Source: Ensembl
  • cerebral cortex development Source: Ensembl
  • chromatin silencing Source: GO_Central
  • DNA damage checkpoint Source: UniProtKB
  • double-strand break repair Source: UniProtKB
  • double-strand break repair via homologous recombination Source: Ensembl
  • double-strand break repair via nonhomologous end joining Source: Reactome
  • meiotic cell cycle Source: UniProtKB-KW
  • nucleosome assembly Source: UniProtKB
  • positive regulation of DNA repair Source: UniProtKB
  • response to ionizing radiation Source: UniProtKB
  • spermatogenesis Source: Ensembl
  • viral process Source: UniProtKB-KW
Complete GO annotation...

Keywords - Biological processi

Cell cycle, DNA damage, DNA recombination, DNA repair, Host-virus interaction, Meiosis

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

BioCyciZFISH:G66-33209-MONOMER.
ReactomeiR-HSA-1221632. Meiotic synapsis.
R-HSA-171306. Packaging Of Telomere Ends.
R-HSA-201722. Formation of the beta-catenin:TCF transactivating complex.
R-HSA-212300. PRC2 methylates histones and DNA.
R-HSA-2299718. Condensation of Prophase Chromosomes.
R-HSA-2559580. Oxidative Stress Induced Senescence.
R-HSA-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-HSA-2559586. DNA Damage/Telomere Stress Induced Senescence.
R-HSA-3214858. RMTs methylate histone arginines.
R-HSA-427359. SIRT1 negatively regulates rRNA Expression.
R-HSA-427389. ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression.
R-HSA-427413. NoRC negatively regulates rRNA expression.
R-HSA-5250924. B-WICH complex positively regulates rRNA expression.
R-HSA-5334118. DNA methylation.
R-HSA-5578749. Transcriptional regulation by small RNAs.
R-HSA-5617472. Activation of anterior HOX genes in hindbrain development during early embryogenesis.
R-HSA-5625886. Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3.
R-HSA-5693565. Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
R-HSA-5693571. Nonhomologous End-Joining (NHEJ).
R-HSA-5693607. Processing of DNA double-strand break ends.
R-HSA-606279. Deposition of new CENPA-containing nucleosomes at the centromere.
R-HSA-69473. G2/M DNA damage checkpoint.
R-HSA-73728. RNA Polymerase I Promoter Opening.
R-HSA-73777. RNA Polymerase I Chain Elongation.
R-HSA-912446. Meiotic recombination.
R-HSA-977225. Amyloid fiber formation.
SIGNORiP16104.

Names & Taxonomyi

Protein namesi
Recommended name:
Histone H2AX
Short name:
H2a/x
Alternative name(s):
Histone H2A.X
Gene namesi
Name:H2AFX
Synonyms:H2AX
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

HGNCiHGNC:4739. H2AFX.

Subcellular locationi

GO - Cellular componenti

  • condensed nuclear chromosome Source: Ensembl
  • extracellular exosome Source: UniProtKB
  • male germ cell nucleus Source: Ensembl
  • nuclear chromatin Source: GO_Central
  • nucleoplasm Source: HPA
  • nucleosome Source: UniProtKB-KW
  • nucleus Source: UniProtKB
  • replication fork Source: Ensembl
  • site of double-strand break Source: MGI
  • XY body Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Chromosome, Nucleosome core, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi141Q → N: Reduced phosphorylation of S-140 in response to DNA damage. 1 Publication1
Mutagenesisi143Y → F: Displays a reduced apoptotic response. S-140 phosphorylation is reduced. 2 Publications1

Organism-specific databases

DisGeNETi3014.
OpenTargetsiENSG00000188486.
PharmGKBiPA29116.

Polymorphism and mutation databases

BioMutaiH2AFX.
DMDMi121992.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000552422 – 143Histone H2AXAdd BLAST142

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineBy similarity1
Modified residuei2PhosphoserineBy similarity1
Modified residuei6N6-acetyllysineBy similarity1
Modified residuei10N6-acetyllysineBy similarity1
Cross-linki14Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Cross-linki16Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei37N6-acetyllysineBy similarity1
Modified residuei122PhosphoserineBy similarity1
Cross-linki135Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei140Phosphoserine; by ATM, ATR and PRKDCCombined sources14 Publications1
Modified residuei143Phosphotyrosine; by WSTF2 Publications1

Post-translational modificationi

Phosphorylated on Ser-140 (to form gamma-H2AX or H2AX139ph) in response to DNA double strand breaks (DSBs) generated by exogenous genotoxic agents and by stalled replication forks, and may also occur during meiotic recombination events and 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) may occur at synaptonemal complexes during leptotene as an ATM-dependent response to the formation of programmed DSBs by SPO11. Ser-140 phosphorylation (H2AX139ph) may subsequently occurs at unsynapsed regions of both autosomes and the XY bivalent during zygotene, downstream of ATR and BRCA1 activation. 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) may occur at sites of DNA-recombination subsequent to activation of 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).16 Publications
Monoubiquitination of Lys-120 (H2AXK119ub) by RING1 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression (By similarity). 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. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.By similarity5 Publications
Acetylation at Lys-37 increases in S and G2 phases. This modification has been proposed to play a role in DNA double-strand break repair (By similarity).By similarity

Keywords - PTMi

Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP16104.
MaxQBiP16104.
PaxDbiP16104.
PeptideAtlasiP16104.
PRIDEiP16104.
TopDownProteomicsiP16104.

PTM databases

iPTMnetiP16104.
PhosphoSitePlusiP16104.
SwissPalmiP16104.

Expressioni

Developmental stagei

Synthesized in G1 as well as in S-phase.

Gene expression databases

BgeeiENSG00000188486.
CleanExiHS_H2AFX.
GenevisibleiP16104. HS.

Organism-specific databases

HPAiCAB012264.
HPA041189.
HPA051647.

Interactioni

Subunit structurei

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. Interacts with numerous proteins required for DNA damage signaling and repair when phosphorylated on Ser-140. These include MDC1, TP53BP1, BRCA1 and the MRN complex, composed of MRE11A, RAD50, and NBN. Interaction with the MRN complex is mediated at least in part by NBN. Also interacts with DHX9/NDHII when phosphorylated on Ser-140 and MCPH1 when phosphorylated at Ser-140 or Tyr-143. Interacts with ARRB2; the interaction is detected in the nucleus upon OR1D2 stimulation. Interacts with Epstein-Barr virus protein EBNA6.6 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Aifm1Q9Z0X12EBI-494830,EBI-5326677From a different organism.
BRCA1P383984EBI-494830,EBI-349905
HIST3H3Q1669511EBI-494830,EBI-358900
LMNAP025453EBI-494830,EBI-351935
MDC1Q1467616EBI-494830,EBI-495644
MRE11AP499596EBI-494830,EBI-396513
NBNO6093414EBI-494830,EBI-494844
PAXIP1Q6ZW49-17EBI-494830,EBI-7521368
PPM1DO152973EBI-494830,EBI-1551512
SMARCA4P515329EBI-494830,EBI-302489
TERF2Q155544EBI-494830,EBI-706637
VRK1Q999863EBI-494830,EBI-1769146

GO - Molecular functioni

  • enzyme binding Source: UniProtKB
  • histone binding Source: UniProtKB

Protein-protein interaction databases

BioGridi109268. 292 interactors.
DIPiDIP-33604N.
IntActiP16104. 172 interactors.
MINTiMINT-1338182.
STRINGi9606.ENSP00000364310.

Structurei

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1YDPX-ray1.90P78-86[»]
2AZMX-ray2.41C/D134-143[»]
2D31X-ray3.20C/F78-86[»]
2DYPX-ray2.50C78-86[»]
3SHVX-ray2.10C/D134-143[»]
3SQDX-ray2.15C/D134-143[»]
3SZMX-ray2.63I/J/K/L/M/N/O/P134-143[»]
3U3ZX-ray1.50B140-143[»]
ProteinModelPortaliP16104.
SMRiP16104.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP16104.

Family & Domainsi

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi140 – 141[ST]-Q motif2

Domaini

The [ST]-Q motif constitutes a recognition sequence for kinases from the PI3/PI4-kinase family.

Sequence similaritiesi

Belongs to the histone H2A family.Curated

Phylogenomic databases

eggNOGiKOG1756. Eukaryota.
COG5262. LUCA.
GeneTreeiENSGT00760000118934.
HOGENOMiHOG000234652.
HOVERGENiHBG009342.
InParanoidiP16104.
KOiK11251.
OMAiTVGPKTP.
OrthoDBiEOG091G0XGD.
PhylomeDBiP16104.
TreeFamiTF300137.

Family and domain databases

Gene3Di1.10.20.10. 1 hit.
InterProiIPR009072. Histone-fold.
IPR002119. Histone_H2A.
IPR007125. Histone_H2A/H2B/H3.
IPR032454. Histone_H2A_C.
IPR032458. Histone_H2A_CS.
[Graphical view]
PfamiPF00125. Histone. 1 hit.
PF16211. Histone_H2A_C. 1 hit.
[Graphical view]
PRINTSiPR00620. HISTONEH2A.
SMARTiSM00414. H2A. 1 hit.
[Graphical view]
SUPFAMiSSF47113. SSF47113. 1 hit.
PROSITEiPS00046. HISTONE_H2A. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P16104-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSGRGKTGGK ARAKAKSRSS RAGLQFPVGR VHRLLRKGHY AERVGAGAPV
60 70 80 90 100
YLAAVLEYLT AEILELAGNA ARDNKKTRII PRHLQLAIRN DEELNKLLGG
110 120 130 140
VTIAQGGVLP NIQAVLLPKK TSATVGPKAP SGGKKATQAS QEY
Length:143
Mass (Da):15,145
Last modified:January 23, 2007 - v2
Checksum:iD4683775C2E6C3A9
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti78R → L in CAG33360 (Ref. 2) Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X14850 mRNA. Translation: CAA32968.1.
CR457079 mRNA. Translation: CAG33360.1.
DQ015918 Genomic DNA. Translation: AAY22178.1.
BC004915 mRNA. Translation: AAH04915.1.
BC011694 mRNA. Translation: AAH11694.1.
BC013416 mRNA. Translation: AAH13416.1.
CCDSiCCDS8410.1.
PIRiS07631.
RefSeqiNP_002096.1. NM_002105.2.
UniGeneiHs.477879.

Genome annotation databases

EnsembliENST00000375167; ENSP00000364310; ENSG00000188486.
ENST00000530167; ENSP00000434024; ENSG00000188486.
GeneIDi3014.
KEGGihsa:3014.
UCSCiuc001pvg.4. human.

Cross-referencesi

Web resourcesi

NIEHS-SNPs
Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X14850 mRNA. Translation: CAA32968.1.
CR457079 mRNA. Translation: CAG33360.1.
DQ015918 Genomic DNA. Translation: AAY22178.1.
BC004915 mRNA. Translation: AAH04915.1.
BC011694 mRNA. Translation: AAH11694.1.
BC013416 mRNA. Translation: AAH13416.1.
CCDSiCCDS8410.1.
PIRiS07631.
RefSeqiNP_002096.1. NM_002105.2.
UniGeneiHs.477879.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1YDPX-ray1.90P78-86[»]
2AZMX-ray2.41C/D134-143[»]
2D31X-ray3.20C/F78-86[»]
2DYPX-ray2.50C78-86[»]
3SHVX-ray2.10C/D134-143[»]
3SQDX-ray2.15C/D134-143[»]
3SZMX-ray2.63I/J/K/L/M/N/O/P134-143[»]
3U3ZX-ray1.50B140-143[»]
ProteinModelPortaliP16104.
SMRiP16104.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109268. 292 interactors.
DIPiDIP-33604N.
IntActiP16104. 172 interactors.
MINTiMINT-1338182.
STRINGi9606.ENSP00000364310.

PTM databases

iPTMnetiP16104.
PhosphoSitePlusiP16104.
SwissPalmiP16104.

Polymorphism and mutation databases

BioMutaiH2AFX.
DMDMi121992.

Proteomic databases

EPDiP16104.
MaxQBiP16104.
PaxDbiP16104.
PeptideAtlasiP16104.
PRIDEiP16104.
TopDownProteomicsiP16104.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000375167; ENSP00000364310; ENSG00000188486.
ENST00000530167; ENSP00000434024; ENSG00000188486.
GeneIDi3014.
KEGGihsa:3014.
UCSCiuc001pvg.4. human.

Organism-specific databases

CTDi3014.
DisGeNETi3014.
GeneCardsiH2AFX.
HGNCiHGNC:4739. H2AFX.
HPAiCAB012264.
HPA041189.
HPA051647.
MIMi601772. gene.
neXtProtiNX_P16104.
OpenTargetsiENSG00000188486.
PharmGKBiPA29116.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1756. Eukaryota.
COG5262. LUCA.
GeneTreeiENSGT00760000118934.
HOGENOMiHOG000234652.
HOVERGENiHBG009342.
InParanoidiP16104.
KOiK11251.
OMAiTVGPKTP.
OrthoDBiEOG091G0XGD.
PhylomeDBiP16104.
TreeFamiTF300137.

Enzyme and pathway databases

BioCyciZFISH:G66-33209-MONOMER.
ReactomeiR-HSA-1221632. Meiotic synapsis.
R-HSA-171306. Packaging Of Telomere Ends.
R-HSA-201722. Formation of the beta-catenin:TCF transactivating complex.
R-HSA-212300. PRC2 methylates histones and DNA.
R-HSA-2299718. Condensation of Prophase Chromosomes.
R-HSA-2559580. Oxidative Stress Induced Senescence.
R-HSA-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-HSA-2559586. DNA Damage/Telomere Stress Induced Senescence.
R-HSA-3214858. RMTs methylate histone arginines.
R-HSA-427359. SIRT1 negatively regulates rRNA Expression.
R-HSA-427389. ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression.
R-HSA-427413. NoRC negatively regulates rRNA expression.
R-HSA-5250924. B-WICH complex positively regulates rRNA expression.
R-HSA-5334118. DNA methylation.
R-HSA-5578749. Transcriptional regulation by small RNAs.
R-HSA-5617472. Activation of anterior HOX genes in hindbrain development during early embryogenesis.
R-HSA-5625886. Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3.
R-HSA-5693565. Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
R-HSA-5693571. Nonhomologous End-Joining (NHEJ).
R-HSA-5693607. Processing of DNA double-strand break ends.
R-HSA-606279. Deposition of new CENPA-containing nucleosomes at the centromere.
R-HSA-69473. G2/M DNA damage checkpoint.
R-HSA-73728. RNA Polymerase I Promoter Opening.
R-HSA-73777. RNA Polymerase I Chain Elongation.
R-HSA-912446. Meiotic recombination.
R-HSA-977225. Amyloid fiber formation.
SIGNORiP16104.

Miscellaneous databases

ChiTaRSiH2AFX. human.
EvolutionaryTraceiP16104.
GeneWikiiH2AFX.
GenomeRNAii3014.
PROiP16104.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000188486.
CleanExiHS_H2AFX.
GenevisibleiP16104. HS.

Family and domain databases

Gene3Di1.10.20.10. 1 hit.
InterProiIPR009072. Histone-fold.
IPR002119. Histone_H2A.
IPR007125. Histone_H2A/H2B/H3.
IPR032454. Histone_H2A_C.
IPR032458. Histone_H2A_CS.
[Graphical view]
PfamiPF00125. Histone. 1 hit.
PF16211. Histone_H2A_C. 1 hit.
[Graphical view]
PRINTSiPR00620. HISTONEH2A.
SMARTiSM00414. H2A. 1 hit.
[Graphical view]
SUPFAMiSSF47113. SSF47113. 1 hit.
PROSITEiPS00046. HISTONE_H2A. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiH2AX_HUMAN
AccessioniPrimary (citable) accession number: P16104
Secondary accession number(s): Q4ZGJ7, Q6IAS5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: January 23, 2007
Last modified: November 30, 2016
This is version 178 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.