Abstract
DNA repair must take place in the context of chromatin, and chromatin modifications and DNA repair are intimately linked. The study of double-strand break repair has revealed numerous histone modifications that occur after induction of a DSB, and modification of the repair factors themselves can also occur. In some cases the function of the modification is at least partially understood, but in many cases it is not yet clear. Although DSB repair is a crucial activity for cell survival, DSBs account for only a small percentage of the DNA lesions that occur over the lifetime of a cell. Repair of single-strand gaps, nicks, stalled forks, alternative DNA structures, and base lesions must also occur in a chromatin context. There is increasing evidence that these repair pathways are also regulated by histone modifications and chromatin remodeling. In this review, we will summarize the current state of knowledge of chromatin modifications that occur during non-DSB repair, highlighting similarities and differences to DSB repair as well as remaining questions.
Highlights
Assaults to the genome are common throughout the lifetime of a cell and DNA damage can occur by endogenous factors, such as reactive oxygen species, base mismatches, and alternative DNA structures, or exogenous factors, such as ultraviolet (UV) radiation and environmental toxins
We have found that lesions at an expanded (CAG)155 repeat are marked by histone modifications
CONCLUDING REMARKS The interplay between histone modifications and DNA repair likely creates a diverse array of cellular responses to DNA damage based on the type of lesion and the preferred pathway of repair for a particular lesion. γH2AX is the first detectable histone modification in response to double-strand breaks (DSBs), but it appears to be a general initial modification, acting as a broad signal of DNA damage, activating signaling cascades in response to stalled forks, gaps, DNA structures, and UV lesions, as well as DSBs
Summary
Assaults to the genome are common throughout the lifetime of a cell and DNA damage can occur by endogenous factors, such as reactive oxygen species, base mismatches, and alternative (non-B form) DNA structures, or exogenous factors, such as ultraviolet (UV) radiation and environmental toxins. Initial γH2AX formation at an HU-stalled replication fork was ATR-dependent; but maintenance of the γH2AX domain at later time points was ATM-dependent, likely occurring once the persistently stalled fork had collapsed into a DSB (Sirbu et al, 2011) While both DSBs and stalled forks are marked by an initial γH2AX histone modification, subsequent chromatin modifications dependent on either ATM or ATR could produce chromatin environments specific to the lesion type, directing repair to the appropriate pathway or influencing the repair process itself. Much research has focused on γH2AX at stalled replication forks, other histone modifications are likely occurring to influence replication fork recovery or repair (Figure 1A) One such modification is phosphorylation of H3-T45 in yeast, a modification observed in response to prolonged replication stress in HU treated cells that is independent of the Mec and Tel kinases and is instead regulated by the Cdc7-Dbf kinase complex (Baker et al, 2010). POST-REPLICATION REPAIR Post-replication repair can be divided into two Rad6-dependent, damage tolerant pathways: error-prone TLS and error-free PRR
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