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histone H2A.x; H2a/x (H2AFX, H2AX)

Function: - variant histone H2A which replaces conventional H2A in a subset of nucleosomes - required for checkpoint-mediated arrest of cell cycle progression in response to low doses of ionizing radiation & for efficient repair of DNA double-strand breaks specifically when modified by C-terminal phosphorylation - phosphorylated on Ser-140 (to form gamma-H2AFX) in response to DNA double-strand breaks generated by exogenous genotoxic agents & by stalled replication forks, & may also occur during meiotic recombination events & immunoglobulin class switching in lymphocytes - phosphorylation can extend up to several thousand nucleosomes from the actual site of the DNA double-strand breaks & may mark the surrounding chromatin for recruitment of proteins required for DNA damage signaling & DNA repair - widespread phosphorylation may also serve to amplify the damage signal or aid repair of persistent lesions - phosphorylation of Ser-140 in response to ionizing radiation is mediated by both ATM & PRKDC while defects in DNA replication induce Ser-140 phosphorylation subsequent to activation of ATR & PRKDC - dephosphorylation of Ser-140 by PP2A is required for DNA double-strand break repair - in meiosis, Ser-140 phosphorylation may occur at synaptonemal complexes during leptotene as an ATM-dependent response to the formation of programmed DNA double-strand breaks by SPO11 - Ser-140 phosphorylation subsequently occurs at unsynapsed regions of both autosomes & the XY bivalent during zygotene, downstream of ATR & BRCA1 activation - Ser-140 phosphorylation may also be required for transcriptional repression of unsynapsed chromatin & meiotic sex chromosome inactivation, whereby the X & Y chromosomes condense in pachytene to form the heterochromatic XY-body - during immunoglobulin class-switch recombination in lymphocytes, Ser-140 phosphorylation may occur at sites of DNA-recombination subsequent to activation of the activation-induced cytidine deaminase AICDA - monoubiquitination of Lys-120 by RING1 & RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression - following DNA double-strand breaks, ubiquitinated through Lys-63 linkage of ubiquitin moieties by the E2 ligase UBE2N & the E3 ligases RNF8 & RNF168, leading to recruitment of DNA repair proteins to sites of DNA damage - monoubiquitination & ionizing radiation-induced Lys-63 linked ubiquitination are distinct events - interacts with numerous proteins required for DNA damage signaling & DNA repair when phosphorylated on Ser-140; these include: MDC1, TP53BP1, BRCA1 & the MRN complex - interaction with the MRN complex is mediated at least in part by NBN - interacts with DHX9/NDHII when phosphorylated on Ser-140 Structure: - the [ST]-Q motif constitutes a recognition sequence for kinases from the PI3/PI4-kinase family - belongs to the histone H2A family Compartment: nucleus Expression: synthesized in G1 as well as in S-phase

General

histone-H2A phosphoprotein

Properties

SIZE: entity length = 143 aa MW = 15 kD COMPARTMENT: cell nucleus MOTIF: acetylation site SITE: N-TERMINUS EFFECTOR-BOUND: acetyl Ser phosphorylation site {S2} Thr phosphorylation site {T121} peptide motif {140-141} MOTIF: Ser phosphorylation site {S140}

Database Correlations

OMIM 601772 UniProt P16104 Pfam PF00125 Entrez Gene 3014 Kegg hsa:3014

References

  1. UniProt :accession P16104
  2. NIEHS-SNPs http://egp.gs.washington.edu/data/h2afx/