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Review
. 2013 Oct;750(1-2):5-14.
doi: 10.1016/j.mrfmmm.2013.07.007. Epub 2013 Jul 31.

Double strand break repair functions of histone H2AX

Ralph Scully  1 , Anyong Xie
Affiliations
Review

Double strand break repair functions of histone H2AX

Ralph Scully et al. Mutat Res. 2013 Oct.

Abstract

Chromosomal double strand breaks provoke an extensive reaction in neighboring chromatin, characterized by phosphorylation of histone H2AX on serine 139 of its C-terminal tail (to form "γH2AX"). The γH2AX response contributes to the repair of double strand breaks encountered in a variety of different contexts, including those induced by ionizing radiation, physiologically programmed breaks that characterize normal immune cell development and the pathological exposure of DNA ends triggered by telomere dysfunction. γH2AX also participates in the evolutionarily conserved process of sister chromatid recombination, a homologous recombination pathway involved in the suppression of genomic instability during DNA replication and directly implicated in tumor suppression. At a biochemical level, the γH2AX response provides a compelling example of how the "histone code" is adapted to the regulation of double strand break repair. Here, we review progress in research aimed at understanding how γH2AX contributes to double strand break repair in mammalian cells.

Keywords: 53BP1; BRCA1; H2AX; Histone code; Homologous recombination; MDC1; Mammalian DSB repair; Mre11/Rad50/Nbs1; Non-homologous end joining; Single strand annealing.

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Figures

Figure 1
Figure 1. Hierarchy of DSB repair pathways
The engagement of DNA end resection plays a critical role in specifying DSB repair pathway selection. Unresected DSBs are candidates for canonical non-homologous end joining (C-NHEJ). The resected DSB can be repaired in an error-free manner by homologous recombination (HR). If this process fails, mutagenic repair via single strand annealing (SSA) or microhomology-mediated end joining (MMEJ) may be engaged. The H2AX-independent roles of BRCA1, 53BP1 and the Mre11/Rad50/Nbs1 (MRN) complex are depicted.
Figure 2
Figure 2. Distinct repair pathways operate on resected DNA ends. A. Homologous recombination/synthesis-dependent strand annealing (SDSA)
Rad51-mediated homologous invasion of the neighboring sister chromatid has potential for error-free repair. B. Single strand annealing (SSA). If two regions of homology (orange boxes) are in close proximity to the DSB, the resected ends may anneal (homologous base pairs marked orange), generating a homologous deletion at the site of breakage. SSA is Rad51-independent. C. Microhomology-mediated end joining (MMEJ). The two resected ends may be stabilized by limited base-pairing (microhomology, base pairs marked red) between the two exposed ssDNA tails of the resected DSB. MMEJ is Rad51-independent.
Figure 3
Figure 3. Double strand break repair functions within the γH2AX chromatin domain
Atm kinase activity propagates the γH2AX signal over hundreds of kilobases of chromatin. In its absence, a more localized γH2AX response is mediated by the related DNA damage response signaling kinases DNA-PKcs and Atr. This Atm-independent γH2AX response can support the function of H2AX in HR/sister chromatid recombination. The Mre11/Rad50/Nbs1 (MRN) complex, BRCA1 and 53BP1 execute DSB repair functions independently of H2AX within the “DNA domain” (see also Figure 1), but their recruitment to extensive chromatin domains flanking the DSB is controlled by γH2AX/MDC1. Non-HR DSB repair functions of γH2AX/MDC1 chromatin include long range rejoining (class switch recombination and fusion of dysfunctional telomeres) and the regulation of DNA end resection.
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