Nucleosome Dynamics as Modular Systems that Integrate DNA Damage and Repair

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).Although we tend to worry the most about environmental sources of DNA damage (e.g., chemical agents, UV radiation, ionizing radiation), it seems likely that much of the DNA repair machinery has evolved to contend with DNA lesions generated by the by-products of cellular metabolism—reactive oxygen species, endogenous alkylating agents, and DNA single- and double-strand breaks resulting from collapsed DNA replication forks or from oxidative destruction of deoxyribose residues (Lindahl and Wood 1999; Lindahl 2000). To combat the diversity of DNA lesions, cells have evolved a complex DNA damage response (DDR) that can engage many different DNA repair pathways, including nucleotide excision repair (NER), base excision repair (BER), DNA mismatch repair (MMR), single-strand annealing (SSA), nonhomologous end joining (NHEJ), and homologous recombination (HR). In eukaryotic cells, each of these repair pathways function in the context of a nucleoprotein structure, chromatin, which can potentially occlude DNA lesions from the repair machinery, and thus can influence the efficiency of repair. Early studies that focused on the response to UV damage, led to the access/repair/restore (ARR) model for repair of DNA lesions in chromatin (Green and Almouzni 2002). A central theme of this model is that chromatin inhibits the repair process, and thus it must be disrupted before or during the repair process, and then chromatin structures must be faithfully restored at the conclusion. What has become clear in the past few years, however, is that chromatin organization also serves a positive role in the DDR, to “prime” DNA repair events, functioning as a regulatory/integration platform that ensures that DNA repair is coordinated with other cellular events (Fig. 1). Here we focus on the repair of DNA double-strand breaks (DSBs), centering on the various mechanisms that facilitate this essential repair event within a chromatin context with a particular emphasis on the nucleosomal level. We envision that the concepts and themes discussed here will also be pertinent to other repair pathways, as discussed in several recent reviews (Adam and Polo 2012; Czaja et al. 2012; Lans et al. 2012; Odell et al. 2013).Open in a separate windowFigure 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.