H2AX (H2A.X Variant Histone)
A key histone variant involved in DNA damage response and genomic stability
Gene Information Card
| Symbol | H2AX |
|---|---|
| Full Name | H2A.X variant histone |
| Gene Type | protein-coding |
| Chromosomal Location | 11q23.3 |
| NCBI Gene ID | 3014 ncbi.nlm.nih.gov/gene/3014 |
| Ensembl ID | ENSG00000188486 |
| UniProt ID | P16104 |
| OMIM ID | 601772 |
| HGNC ID | 4739 |
| Aliases | H2A.X, H2AFX, H2A histone family member X |
Description
H2AX is a member of the histone H2A family that plays a central role in the DNA damage response. Upon DNA double-strand breaks, H2AX is rapidly phosphorylated at serine 139 (forming γ-H2AX) by ATM, ATR, and DNA-PK kinases. γ-H2AX serves as a docking site for DNA repair proteins, facilitating checkpoint activation and repair. Loss or mutation of H2AX leads to genomic instability, increased sensitivity to ionizing radiation, and predisposition to cancer.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Breast cancer | Defective H2AX phosphorylation impairs DNA repair, increasing mutation accumulation | ClinVar, COSMIC |
| Ataxia telangiectasia | ATM deficiency prevents H2AX phosphorylation, disrupting DNA damage signaling | OMIM |
| Lung cancer | Somatic H2AX mutations and reduced expression linked to genomic instability | COSMIC |
| Colorectal cancer | H2AX loss associated with microsatellite instability and poor prognosis | NCBI Gene, COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 28.5 | High |
| Bone marrow | 18.2 | Medium |
| Lymph node | 15.0 | Medium |
| Brain | 6.3 | Low |
| Liver | 4.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 22.1 | Cervical cancer cell line |
| K562 | 19.8 | Leukemia cell line |
| A549 | 16.4 | Lung cancer cell line |
| MCF7 | 14.2 | Breast cancer cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.416A>G (p.Tyr139Cys) | Missense | Rare | Impaired phosphorylation and DNA repair |
| c.1A>G (p.Met1Val) | Start loss | Very rare | Loss of protein expression |
| c.328C>T (p.Arg110*) | Nonsense | Rare | Truncated protein, loss of function |
Mutation functional classification
Loss of Function (LOF)
H2AX loss-of-function mutations impair γ-H2AX formation, compromising DNA repair and promoting genomic instability.
Gain of Function (GOF)
No well-characterized gain-of-function mutations reported.
Dominant Negative (DN)
Some missense mutations (e.g., Tyr139Cys) may act dominant-negatively by interfering with wild-type H2AX phosphorylation.
View complete mutation data：
Gene Ontology (GO)
| • DNA repair | • double-strand break repair |
| • chromatin organization | • nucleosome assembly |
| • DNA damage response | • signal transduction by p53 class mediator |
Pathways
• ATM signaling pathway
• DNA double-strand break repair
• p53 signaling pathway
• Apoptosis
Protein Summary
Histone H2AX is a 142-amino acid protein that differs from canonical H2A by a unique C-terminal tail containing a conserved SQ motif (Ser139-Gln140). Upon DNA damage, Ser139 is phosphorylated to generate γ-H2AX, which spreads megabases around break sites. γ-H2AX recruits MDC1, 53BP1, and BRCA1, amplifying the damage signal and promoting repair by homologous recombination or non-homologous end joining. H2AX is essential for maintaining genomic integrity and its dysfunction is linked to multiple cancers.
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