Nucleosome dynamics as modular systems that integrate DNA damage and repair

Abstract

By some estimates, a eukaryotic cell must repair up to 10,000 DNA lesions per cell cycle to counteract endogenous sources of DNA damage. Exposure to environmental toxins, UV sources, or other radiations only increases this enormous number. Failure to repair such lesions can lead to a deleterious mutation rate, genomic instability, or cell death. The timely and efficient repair of eukaryotic DNA damage is further complicated by the realization that DNA lesions must be detected and repaired in the context of chromatin with its complex organization within the nucleus. Numerous studies have shown that chromatin packaging can inhibit nearly all repair pathways, and recent work has defined specific mechanisms that facilitate DNA repair within the chromatin context. In this review, we provide a broad overview of chromatin regulatory mechanisms, mainly at the nucleosomal level, and then focus on recent work that elucidates the role of chromatin structure in regulating the timely and efficient repair of DNA double-strand breaks (DSBs).

Figure 1.

Access/prime/repair/restore model for the role of chromatin in the DDR. Chromatin remodeling and histone modification enzymes regulate both the accessibility of the lesion to repair factors as well as providing a platform for signaling repair events to other cellular processes. See text for details.

Figure 2.

Histone modifications orchestrate binding of key DDR factors to DSB chromatin. (A) Histone modifications and their associated enzymes at DSB chromatin. (B) Histone modifications and their binding partners or regulators. See text for details. Note that the figure illustrates the ubiquitination-dependent recruitment of 53BP1 to DSBs, but it is not thought to directly bind to ubiquitinylated proteins.