H2A.X

SECTIONS

1 - Developmental stage
2 - Domain
3 - Function
4 - Post-translational modifications
5 - Sequence similarities
6 - Cellular localization
7 - Alternative names
8 - Database links
9 - Target type
10 - Primary research area
11 - Other research areas
12 - Molecular weight

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.

Function

The protein expressed by the H2AX gene is a variant histone H2A that replaces conventional H2A in certain nucleosomes, which are responsible for wrapping and compacting DNA into chromatin. This compaction limits DNA accessibility to cellular machineries that require DNA as a template, placing histones at the center of transcription regulation, DNA repair, DNA replication, and chromosomal stability. DNA accessibility is controlled through a complex array of post-translational histone modifications, known as the histone code, and nucleosome remodeling. The H2AX protein is essential for the checkpoint-mediated arrest of cell cycle progression in response to low doses of ionizing radiation and for the efficient repair of DNA double strand breaks (DSBs), particularly when it undergoes C-terminal phosphorylation. This supplementary information is collated from multiple sources and compiled automatically.

Post-translational modifications

Phosphorylated by VRK1 (PubMed:31527692). 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).

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.

Acetylation at Lys-6 (H2AXK5ac) by KAT5 component of the NuA4 histone acetyltransferase complex promotes NBN/NBS1 assembly at the sites of DNA damage (PubMed:17709392, PubMed:26438602). 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).