When repair meets chromatin. First in series on chromatin dynamics

Abstract

In eukaryotic cells, the inheritance of both the DNA sequence and its organization into chromatin is critical to maintain genome stability. This maintenance is challenged by DNA damage. To fully understand how the cell can tolerate genotoxic stress, it is necessary to integrate knowledge of the nature of DNA damage, its detection and its repair within the chromatin environment of a eukaryotic nucleus. The multiplicity of the DNA damage and repair processes, as well as the complex nature of chromatin, have made this issue difficult to tackle. Recent progress in each of these areas enables us to address, both at a molecular and a cellular level, the importance of inter-relationships between them. In this review we revisit the 'access, repair, restore' model, which was proposed to explain how the conserved process of nucleotide excision repair operates within chromatin. Recent studies have identified factors potentially involved in this process and permit refinement of the basic model. Drawing on this model, the chromatin alterations likely to be required during other processes of DNA damage repair, particularly double-strand break repair, are discussed and recently identified candidates that might perform such alterations are highlighted.

Fig. 1. (A) The original three-step ARR model for NER to explain how repair can be achieved at the nucleosomal level. To overcome inhibition by nucleosome structure (depicted in blue), the first stage in the repair process is removal or remodelling of nucleosomes to permit access to the DNA lesion (the star), here depicted for a few nucleosomes. After repair of the DNA, the original chromatin structure must be restored to ensure that epigenetic information is maintained. (B and C) An expansion of the original model to highlight factors that may be required for alterations in chromatin structure during the different enzymatic stages that comprise NER (B) and HR (C). Although only one additional stage is depicted in each case, this model is continuously evolving, and as our understanding of the interplay between chromatin dynamics and repair increases it will be adapted to include a greater degree of complexity.

Fig. 2. Proteins that connect repair and chromatin. This table lists, in alphabetical order, factors that link repair and chromatin dynamics. Each protein’s roles in repair and other chromatin processes are highlighted. The central arrow represents the direction in which the connection was discovered: left to right for known chromatin proteins for which a DNA repair role was subsequently discovered, and right to left in the alternative case. The central numbers refer to the references in which this connection was made, and correspond to: 1, Ura et al., 2001; 2, Tyler et al., 1999; 3, Emili et al., 2001; 4, Gaillard et al., 1996; 5, Kaufman et al., 1997; 6, Citterio et al., 2000; 7, Rogakou et al., 1998; 8, Shen et al., 2000; 9, Martin et al., 1999; 10, Moggs et al., 2000; 11, Hasan et al., 2001; 12, Eisen et al., 1995; 13, McAinsh et al., 1999; 14, Mills et al., 1999; 15, Brand et al., 2001; 16, Ikura et al., 2000; 17, Datta et al., 2001.

Geneviève Almouzni & Catherine M. Green