INSIGHTS FROM MODEL SYSTEMS Cell-Cycle Regulation of Mammalian DNA Double-Strand-Break Repair

The structural integrity of chromosomal DNA is of crosslinks (Friedberg et al. 1995), in chromosomal DNA. In particular, DNA DSBs appear to be the preparamount importance to survival, and, consequently, all living cells have evolved mechanisms for the repair dominant cytotoxic lesions, since even a single unrepaired DNA DSB can be a lethal event (Frankenbergof DNA lesions. This paradigm recently has been made tragically clear, with the identification of a series Schwager and Frankenberg 1990). Similarly, the development of the mammalian immune system is dependent of human cancer-predisposition syndromes that can arise from mutations in DNA-repair genes. Thus, deon a site-specific DNA-recombination process, called ‘‘lymphoid V(D)J recombination,’’ that assembles the fects in the nucleotide-excision repair pathway result in xeroderma pigmentosum, which presents with a noncontiguous genomic segments (variable [V], diversity [D], and joining [J] elements) to create immunoglobulin greatly increased incidence of skin cancer (Wood 1996). Similarly, defects in the mismatch repair pathand T-cell receptor genes (Lewis 1994). Analyses of V(D)J recombination products have proven that DNA way predispose affected individuals to colon cancer and to other cancers (Kolodner 1995). Recently, it has DSBs are an essential intermediate in the V(D)J-reaction mechanism (Weaver and Alt 1997). Thus, the repair of become clear that defects in a third major DNA-repair pathway, DNA double-strand-break (DSB) repair, DNA DSBs is an integral feature of IR sensitivity and of V(D)J recombination. which have long been known to be associated with xray hypersensitivity and immune deficiency, probably Intriguingly, a variety of pathways that act at different times during the cell cycle and that are likely to underlie the familial predisposition to breast cancer and to ovarian cancer (Kinzler and Vogelstein 1997). be very sensitive to the proliferative and ploidy states of the cell have evolved to ensure that such DSBs are This exciting revelation, coupled with the widespread clinical use of radiation exposure for cancer therapy, repaired effectively. Recent work in mammalian and in yeast model systems suggests that at least two dishas prompted a sudden and intense interest in DNA DSB repair. This review will focus on the evidence tinct pathways, mediated by as many as four discrete complexes, facilitate the repair of DSBs (Petrini et al. that demonstrates that there are several different mechanisms of DNA DSB repair, which operate dur1997; Kanaar and Hoeijmakers 1997). In one pathway, nonhomologous recombinational repair, DNA ing distinct phases of the cell cycle. It has been known for several years that, in mammals, repair requires no or very little homology on the ends of the strands being rejoined. Two discrete complexes defects in DNA DSB repair manifest themselves in two phenotypes, ionizing-radiation (IR) hypersensitivity and implicated in this pathway, the DNA-dependent protein kinase (DNA-PK) complex and the RAD50 comimmune deficiencies. These two seemingly unrelated biological processes, in fact, are linked by the requirement plex, act primarily during the G1/early S phase of the cell cycle. In homologous recombinational repair, exof DNA DSBs as reaction intermediates. Thus, the exposure of mammalian cells to IR induces lesions, such as tensive homology is required between the region with the DSB and a template (usually a sister chromatid strand scissions, single-stranded breaks, DSBs, and base or a homologous chromosome) from which repair is directed. This type of repair is performed either by the RAD52 complex, which acts predominantly durReceived July 14, 1997; accepted for publication August 15, 1997. ing the late S/G2 phase, or by the BRCA1/2 complex, Address for correspondence and reprints: Dr. Eric A. Hendrickson, which appears to act during the S phase. Other pathBox G-J1, Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912. E-mail: ways for DSB repair (single-strand annealing [Lin et Eric_Hendrickson@brown.edu al. 1984], retrotransposon capping [Moore and Haber This article represents the opinion of the author and has not been 1996a; Teng et al. 1996], and de novo telomere addipeer reviewed. tion [Kramer and Haber 1993]) apparently are less 1997 by The American Society of Human Genetics. All rights reserved. 0002-9297/97/6104-0004$02.00 active in mammals and will not be discussed here.