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Protein

Histone H2AX

Gene

H2AFX

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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: GO_Central
  • enzyme binding Source: UniProtKB
  • histone binding Source: UniProtKB
  • protein heterodimerization activity Source: InterPro

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

Keywordsi

Molecular functionDNA-binding
Biological processCell cycle, DNA damage, DNA recombination, DNA repair, Host-virus interaction, Meiosis

Enzyme and pathway databases

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-8936459 RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function
R-HSA-8939236 RUNX1 regulates transcription of genes involved in differentiation of HSCs
R-HSA-9018519 Estrogen-dependent gene expression
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

EuPathDBiHostDB:ENSG00000188486.3
HGNCiHGNC:4739 H2AFX
MIMi601772 gene
neXtProtiNX_P16104

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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
Cross-linki120Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei122PhosphoserineBy similarity1
Cross-linki128Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
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
ProteomicsDBi53286
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 MRE11, 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.5 Publications
(Microbial infection) Interacts with Epstein-Barr virus protein EBNA6.1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

  • enzyme binding Source: UniProtKB
  • histone binding Source: UniProtKB
  • protein heterodimerization activity Source: InterPro

Protein-protein interaction databases

BioGridi109268, 308 interactors
CORUMiP16104
DIPiDIP-33604N
ELMiP16104
IntActiP16104, 185 interactors
MINTiP16104
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
GeneTreeiENSGT00910000143981
HOGENOMiHOG000234652
HOVERGENiHBG009342
InParanoidiP16104
KOiK11251
OMAiVIVECAC
OrthoDBiEOG091G0XGD
PhylomeDBiP16104
TreeFamiTF300137

Family and domain databases

CDDicd00074 H2A, 1 hit
Gene3Di1.10.20.10, 1 hit
InterProiView protein in InterPro
IPR009072 Histone-fold
IPR002119 Histone_H2A
IPR007125 Histone_H2A/H2B/H3
IPR032454 Histone_H2A_C
IPR032458 Histone_H2A_CS
PfamiView protein in Pfam
PF00125 Histone, 1 hit
PF16211 Histone_H2A_C, 1 hit
PRINTSiPR00620 HISTONEH2A
SMARTiView protein in SMART
SM00414 H2A, 1 hit
SUPFAMiSSF47113 SSF47113, 1 hit
PROSITEiView protein in PROSITE
PS00046 HISTONE_H2A, 1 hit

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

Similar proteinsi

Entry informationi

Entry nameiH2AX_HUMAN
AccessioniPrimary (citable) accession number: P16104
Secondary accession number(s): Q4ZGJ7, Q6IAS5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: January 23, 2007
Last modified: June 20, 2018
This is version 192 of the entry and version 2 of the sequence. See 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

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