Alternative titles; symbols
HGNC Approved Gene Symbol: H2AX
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:119,093,874-119,095,465 (from NCBI)
Histones wrap DNA to form nucleosome particles that compact eukaryotic genomes. Each nucleosome core particle consists of DNA wrapped by an octamer containing 2 molecules each of the highly conserved histones H2A (see 613499), H2B (see 609904), H3 (see 602810), and H4 (see 602822). H1 histones (see 142709) occupy the linker DNA between nucleosomes. Canonical histone genes are clustered in repeat arrays and their transcription is tightly coupled to DNA replication. In contrast, noncanonical variant histone genes are found singly in the genome, are constitutively expressed, and encode histones that differ in primary amino acid sequence from their canonical paralogs. Unlike canonical histones that function primarily in genome packaging and gene regulation, variant histones have roles in DNA repair, meiotic recombination, chromosome segregation, transcription initiation and termination, sex chromosome condensation, and sperm chromatin packaging. H2AFX is variant histone of the H2A family (review by Talbert and Henikoff, 2010).
For additional background information on histones, histone gene clusters, and the H2A histone family, see HIST1H2AA (613499).
Ivanova et al. (1994) stated that this gene, termed H2A.X by them, is 1 of 3 whose synthesis is not linked to DNA replication. They stated that H2AX is encoded by an alternatively processed transcript that yields 2 mRNA species, a 0.6-kb stemloop transcript indistinguishable from those of replication-linked histones, and a 1.6-kb read-through polyadenylated transcript. Ivanova et al. (1994) noted that the gene encodes a 142-amino acid protein having a unique C-terminal sequence, QASQEY, which has been conserved from lower eukaryotes.
Chen et al. (2000) reported that the Nijmegen breakage syndrome protein (NBS1; 602667) and phosphorylated H2AX (gamma-H2AX), which associate with irradiation-induced DNA double-strand breaks (DSBs), are also found at sites of V(D)J (variable, diversity, joining) recombination-induced DSBs. In developing thymocytes, NBS1 and gamma-H2AX form nuclear foci that colocalize with the T-cell receptor-alpha (TCRA; see 186880) locus in response to recombination-activating gene-1 (RAG1; 179615) protein-mediated V(D)J cleavage. Chen et al. (2000) concluded that their results suggest that surveillance of T-cell receptor recombination intermediates by NBS1 and gamma-H2AX may be important for preventing oncogenic translocations.
Class switch recombination is a region-specific DNA recombination reaction that replaces one immunoglobulin heavy-chain constant region gene with another. This enables a single variable region gene to be used in conjunction with different downstream heavy-chain constant region genes, each having a unique biologic activity. Activation-induced cytidine deaminase (AID; 605257), a putative RNA editing enzyme, is required for this action. Petersen et al. (2001) reported that the NBS1 protein and gamma-H2AX, which facilitate DNA double-strand break repair, form nuclear foci at the heavy-chain constant region in the G1 phase of the cell cycle in cells undergoing class switch recombination. Class switch recombination is impaired in H2AX -/- mice. Localization of NBS1 and gamma-H2AX to the immunoglobulin heavy-chain locus during class switch recombination is dependent on AID. In addition, AID is required for induction of switch region-specific DNA lesions that precede class switch recombination. Petersen et al. (2001) concluded that AID functions upstream of the DNA modifications that initiate class switch recombination.
Chowdhury et al. (2005) found that protein phosphatase-2A (PP2A) is involved in removing gamma-H2AX from DNA foci during double-stranded break repair. The PP2A catalytic subunit (PPP2CA; 176915) and gamma-H2AX coimmunoprecipitated from human cell lines and colocalized in DNA damage foci, and PP2A dephosphorylated gamma-H2AX in vitro. Recruitment of PPP2CA to DNA damage foci was H2AX dependent. Inhibition of PPP2CA by RNA interference led to the persistence of gamma-H2AX foci, inefficient DNA repair, and cells that were hypersensitive to DNA damage.
Gorgoulis et al. (2005) analyzed a panel of human lung hyperplasias, all of which retained wildtype p53 (191170) genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and CHK2 (604373) phosphorylation, p53 accumulation, focal staining of p53 binding protein-1 (53BP1; 605230), and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis. A DNA damage response was also observed in dysplastic nevi and in human skin xenografts, in which hyperplasia was induced by overexpression of growth factors. Both lung and experimentally-induced skin hyperplasias showed allelic imbalance at loci that are prone to DNA double-strand break formation when DNA replication is compromised (common fragile sites). Gorgoulis et al. (2005) proposed that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability, and selective pressure for p53 mutations.
By examining immunoglobulin heavy chain (see 147100) class switch recombination in mouse B-lymphocytes deficient in H2ax, Atm (607585), 53bp1, or Mdc1 (607593), Franco et al. (2006) determined that these factors promote end joining and thereby prevent DNA double-strand breaks from progressing into chromosomal breaks and translocations.
Keogh et al. (2006) described a 3-protein complex in S. cerevisiae, which they called HTP-C for histone H2A phosphatase complex, containing the phosphatase Pph3 that regulates the phosphorylation status of gamma-H2AX in vivo and efficiently dephosphorylates gamma-H2AX in vitro. Gamma-H2AX is lost from chromatin surrounding a double-strand break independently of the HTP-C, indicating that the phosphatase targets gamma-H2AX after its displacement from DNA. The dephosphorylation of gamma-H2AX by the HTP-C is necessary for efficient recovery from the DNA damage checkpoint.
Using a combination of proteomics, cytology, and functional analysis in C. elegans, Chu et al. (2006) reduced 1,099 proteins copurified with spermatogenic chromatin to 132 proteins for functional analysis. This strategy to find fertility factors conserved from C. elegans to mammals achieved its goal: of mouse gene knockouts corresponding to nematode proteins, 37% (7 of 19) cause male sterility. This list includes PPP1CC (176914), H2AX, SON (182465), TOP1 (126420), DDX4 (605281), DBY (400010), and CENPC (117141).
GABA(A) receptors signal through S-phase checkpoint kinases of the phosphatidylinositol-3-OH kinase-related kinase family and the histone variant H2AX. This signaling pathway critically regulates proliferation independently of differentiation, apoptosis, and overt damage to DNA. Andang et al. (2008) demonstrated that autocrine/paracrine gamma-aminobutyric acid (GABA) signaling by means of GABA(A) receptors negatively controls embryonic stem (ES) cell and peripheral neural crest stem (NCS) cell proliferation, preimplantation embryonic growth, and proliferation in the boundary-cap stem cell niche, resulting in an attenuation of neuronal progenies from this stem cell niche. Activation of GABA(A) receptors leads to hyperpolarization, increased cell volume, and accumulation of stem cells in S phase, thereby causing a rapid decrease in cell proliferation. Andang et al. (2008) concluded that their results indicated the presence of a fundamentally different mechanism of proliferation control in these stem cells, in comparison with most somatic cells, involving proteins in the DNA damage checkpoint pathway.
Ayoub et al. (2008) identified a dynamic change in chromatin that promotes H2AX phosphorylation in mammalian cells. DNA breaks swiftly mobilized heterochromatin protein-1-beta (HP1-beta; 604511), a chromatin factor bound to histone H3 methylated on lysine-9 (H3K9me; see 602810). Local changes in histone tail modifications were not apparent. Instead, phosphorylation of HP1-beta on amino acid thr51 accompanied mobilization, releasing HP1-beta from chromatin by disrupting hydrogen bonds that fold its chromodomain around H3K9me. Inhibition of casein kinase-2 (CK2; see 115442), an enzyme implicated in DNA damage sensing and repair, suppressed thr51 phosphorylation and HP1-beta mobilization in living cells. CK2 inhibition, or a constitutively chromatin-bound HP1-beta mutant, diminished H2AX phosphorylation. Ayoub et al. (2008) concluded that their findings revealed a signaling cascade that helps to initiate the DNA damage response, altering chromatin by modifying a histone code mediator protein, HP1, but not the code itself.
During the double-strand break response, mammalian chromatin undergoes reorganization demarcated by H2A.X ser139 phosphorylation. Xiao et al. (2009) reported a regulatory mechanism mediated by WSTF (BAZ1B; 605681), a component of the WICH (WSTF-ISWI ATP-dependent chromatin-remodeling) complex. Xiao et al. (2009) showed that WSTF has intrinsic tyrosine kinase activity by means of a domain that shares no sequence homology to any known kinase fold. They showed that WSTF phosphorylates tyr142 of H2A.X, and that WSTF activity has an important role in regulating several events that are critical for the DNA damage response. Xiao et al. (2009) concluded that their work demonstrated a novel mechanism that regulates the DNA damage response and expanded the knowledge of domains that contain intrinsic tyrosine kinase activity. The kinase domain of WSTF consists of an N motif containing the conserved WAC domain, and a novel C motif.
Cook et al. (2009) reported that the protein-tyrosine phosphatase EYA (601653) is involved in promoting efficient DNA repair rather than apoptosis in response to genotoxic stress in mammalian embryonic kidney cells by executing a damage signal-dependent dephosphorylation of an H2AX carboxy-terminal tyrosine phosphate (Y142). This posttranslational modification determines the relative recruitment of either DNA repair or proapoptotic factors to the tail of serine-phosphorylated histone H2AX and allows it to function as an active determinant of repair/survival versus apoptotic responses to DNA damage, revealing an additional phosphorylation-dependent mechanism that modulates survival/apoptotic decisions during mammalian organogenesis.
In vivo, Helmink et al. (2011) demonstrated that in murine cells the histone protein H2AX prevents nucleases other than Artemis (605988) from processing hairpin-sealed coding ends; in the absence of H2AX, CtIP (604124) can efficiently promote the hairpin opening and resection of DNA ends generated by RAG (see 179615) cleavage. This CtIP-mediated resection is inhibited by gamma-H2AX and by MDC1 (607593), which binds to gamma-H2AX in chromatin flanking DNA double-strand breaks. Moreover, the ataxia-telangiectasia mutated kinase (ATM; 607585) activates antagonistic pathways that modulate this resection. CtIP DNA end resection activity is normally limited to cells at postreplicative stages of the cell cycle, in which it is essential for homology-mediated repair. In G1-phase lymphocytes, DNA ends that are processed by CtIP are not efficiently joined by classical nonhomologous end joining and the joints that do form frequently use microhomologies and show significant chromosomal deletions. Helmink et al. (2011) concluded that H2AX preserves the structural integrity of broken DNA ends in G1-phase lymphocytes, thereby preventing these DNA ends from accessing repair pathways that promote genomic instability.
Pei et al. (2011) found that H4K20 methylation actually increases locally upon the induction of double-strand breaks and that methylation of H4K20 at double-strand breaks is mediated by the histone methyltransferase MMSET (602952) in mammals. Downregulation of MMSET significantly decreases H4K20 methylation at double-strand breaks and the subsequent accumulation of 53BP1 (605230). Furthermore, Pei et al. (2011) found that the recruitment of MMSET to double-strand breaks requires the gamma-H2AX-MDC1 pathway; specifically, the interaction between the MDC1 BRCT domain and phosphorylated ser102 of MMSET. Thus, Pei et al. (2011) proposed that a pathway involving gamma-H2AX-MDC1-MMSET regulates the induction of H4K20 methylation on histones around double-strand breaks, which, in turn, facilitates 53BP1 recruitment.
Using small interfering RNA-mediated knockdown studies in human osteosarcoma cells, Hu et al. (2013) showed that ZNF668 (617103) promoted TIP60 (KAT5; 601409)-mediated H2AX lys5 acetylation and chromatin relaxation to facilitate homologous recombination-directed repair of double-strand breaks caused by ionizing radiation.
Ivanova et al. (1994) cloned the human genomic region encompassing the H2AX gene. They reported that the upstream region of this gene contains 2 CCAAT boxes, the more proximal of which shares homology and binding factors with another replication-unlinked histone, H2A.Z (142763).
Ivanova et al. (1994) mapped the human H2AX gene to chromosome 11q23.2-q23.3 using fluorescence in situ hybridization. This localization is not near clusters of other human histone genes on chromosomes 1, 6, and 12. They also noted that the downstream sequence of the H2AX gene overlaps the hydroxymethylbilane synthase gene (HMBS; 609806), which has also been mapped to chromosome 11q.
Porcher and Grandchamp (1995) reported that in both mouse and human, the H2AX and AIP genes are arranged in an opposite, tail-to-tail, orientation, with less than 340 nucleotides separating their 3-prime ends. They mapped mouse H2AX to chromosome 9 based on its proximity to the previously mapped mouse AIP, or UPS, gene.
Srivastava et al. (2008) found an alteration of the H2AFX gene copy number in 25 (37%) of 65 breast cancer (114480) tissues derived from patients with sporadic forms of the disorder. Gene deletion accounted for 19 (29%) of total cases and gene amplification for 6 (9%). Patients with estrogen (ES1R1; 133430) and progesterone receptor (PGR; 607311)-positive tumors had more significantly altered copy numbers of H2AFX compared to those with ER/PR-negative tumors. None of the tissues contained H2AFX sequence alterations.
Celeste et al. (2002) generated mice deficient in H2AX by targeted disruption. Although H2AX is not essential for irradiation-induced cell-cycle checkpoints, H2ax -/- mice were radiation sensitive, growth retarded, and immune deficient, and mutant males were infertile. These pleiotropic phenotypes were associated with chromosomal instability, repair defects, and impaired recruitment of NBS1 (602667), TP53BP1 (605230), and BRCA1 (113705), but not RAD51 (179617), to irradiation-induced foci. Thus, Celeste et al. (2002) concluded that H2AX is critical for facilitating the assembly of specific DNA-repair complexes on damaged DNA.
Phosphorylation of the human histone variant H2AX and H2Av, its homolog in Drosophila melanogaster, occurs rapidly at sites of DNA double-strand breaks. Kusch et al. (2004) demonstrated that the Drosophila Tip60 (HTATIP; 601409) chromatin-remodeling complex acetylated nucleosomal phospho-H2Av and exchanged it with an unmodified H2Av. Both the histone acetyltransferase Tip60 as well as the ATPase Domino/p400 (606265) catalyzed the exchange of phospho-H2Av. Thus, Kusch et al. (2004) concluded that their data reveal a previously unknown mechanism for selective histone exchange that uses the concerted action of 2 distinct chromatin-remodeling enzymes within the same multiprotein complex.
During meiotic prophase in males, the X and Y chromosomes condense to form a macrochromatin body, termed the sex (or XY) body, within which X- and Y-linked genes are transcriptionally repressed. Fernandez-Capetillo et al. (2003) found that H2ax-null mouse spermatocytes did not form a sex body and failed to undergo sex chromosome inactivation. Moreover, apoptotic elimination of H2ax-null spermatocytes occurred at the pachytene stage via a p53 (191170)-independent pathway. Fernandez-Capetillo et al. (2003) concluded that H2AX is essential for condensation and silencing of the sex chromosomes during male meiosis.
Fernandez-Capetillo et al. (2003) found that H2ax was dispensable for mitotic telomere maintenance and chromosome fusions arising from either shortened or deprotected telomeres. However, telomeres of H2ax-deficient mouse spermatocytes showed abnormally lengthy clustering along the nuclear periphery during the first meiotic prophase. Atm (607585)-null leptotene/zygotene-stage spermatocytes showed a similar lengthy telomere clustering in addition to absence of H2ax staining. Fernandez-Capetillo et al. (2003) concluded that ATM facilitates telomere-promoted homolog pairing via phosphorylation of H2AX.
Celeste et al. (2003) found that loss of a single H2ax allele compromised genomic integrity and enhanced susceptibility to cancer in mice lacking p53. Compared with heterozygotes, tumors arose earlier in the H2ax homozygous null background, and H2ax -/- p53 -/- lymphomas harbored an increased frequency of clonal nonreciprocal translocations and amplifications, including complex rearrangements that juxtaposed the Myc oncogene (190080) to antigen receptor loci. Restoration of the H2ax-null allele with wildtype H2ax restored genomic stability and radiation resistance, but this effect was abolished by substitution of the conserved serine phosphorylation sites in H2ax with alanine or glutamic acid. Celeste et al. (2003) concluded that H2AX is a genomic caretaker that requires the function of both alleles for optimal protection against tumorigenesis. Bassing et al. (2003) presented similar findings.
Hypoxia induces neovascularization and can also induce a DNA-damage response. Economopoulou et al. (2009) showed that hypoxia-induced replication-associated generation of phosphorylated gamma-H2AX in human umbilical vein endothelial cells in vitro and in mice. In mice, this was associated with retinal neovascularization. H2ax-null mice showed decreased endothelial cell proliferation under hypoxic conditions, including deficient hypoxia-induced neovascularization in proliferative retinopathy, in response to hind-limb ischemia, and in tumor angiogenesis. In contrast, developmental angiogenesis was not affected. Endothelial-specific H2ax deletion resulted in reduced hypoxia-driven retinal neovascularization and tumor neovascularization. Economopoulou et al. (2009) suggested that H2AX and activation of the DNA repair response is needed for endothelial cells to maintain their proliferation under hypoxic conditions, and that H2AX is crucial for hypoxia-driven neovascularization.
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