CDK activity first increases in late G1 to bring about S phase and it is strongly activated in late G2 to drive entry into mitosis.
Recent studies have indicated that cyclin-dependent kinase (CDK) activity plays a pivotal role in that control ( Aylon et al., 2004 Henderson et al., 2006 Ira et al., 2004). While the underlying reasons for the bias towards one DSB repair pathway over the other are clear, the exact mechanism through which specific repair modes are coordinated with cell-cycle stage has remained enigmatic. A bias for DSB repair pathways also exists in meiosis, in which HR repair of programmed DSBs is favored because it generates genetic diversity and forms chiasmata between homologous chromosomes that are essential for their proper segregation. In principle either pathway can suffice in G2, although HR is favored in yeasts, presumably because it is error free. Replication fork breakage during S phase creates a single-ended break (SEB) that cannot be repaired by NHEJ, necessitating repair by a fork recapture mechanism dependent on HR ( McGlynn and Lloyd, 2002). In haploid organisms the absence of a sister chromatid during G1 precludes HR repair in unique DNA sequences, leaving NHEJ as the only viable option. There are logical reasons for this pattern of regulation. Recent studies of model organisms support the long-standing notion that the two modes of DSB repair are controlled during the cell cycle, with NHEJ favored in the pre-replicative phase and HR favored in post-replicative phases ( Aylon et al., 2004 Ferreira and Cooper, 2004 Ira et al., 2004).
These are clinically related diseases of which NBS is characterized by chromosomal instability, radiation sensitivity, microcephaly, growth retardation, immunodeficiency, and predisposition to cancer. Notably, hypomorphic mutations of Mre11 and Nbs1 cause Ataxia-Telangiectasia-Like Disorder (ATLD) and Nijmegen Breakage Syndrome (NBS), respectively ( D’Amours and Jackson, 2002). Defects in either pathway have profound effects on human health in ways that are directly linked to genome instability. Their controlling elements include the Ku70-Ku80 DNA end-binding complex required for NHEJ and the Mre11-Rad50-Nbs1 (MRN) complex required for HR. The critical components of these pathways are evolutionary conserved from yeast to humans. Eukaryotes have two primary mechanisms of repairing DNA double-strand breaks (DSBs): non-homologous end joining (NHEJ) and homologous recombination (HR).
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