IDENTIFICATION OF GENES INVOLVED IN REPAIR OF DNA DOUBLE-STRAND BREAKS IN MAMMALIAN-CELLS

At least two mechanisms of DNA double-strand break (DSB) repair operat e in mammalian cells. Homologous recombination, which plays a major ro le in lower organisms, plays a less significant role in higher organis ms. In contrast, the majority of DSBs in mammalian cells are rejoined by a mechanism, termed non-homologous end joining (NHEJ), that does no t depend upon extensive regions of homology. This process is also used to rejoin site-specific DSBs introduced during V(D)J recombination. F rom the analysis of defective rodent mutants, four proteins (Ku70, Ru8 0, DNA-PKcs and Xrcc4) that function in this process in mammalian cell s have been identified. DNA ligase IV is also strongly implicated sinc e it associates strongly with XRCC4, and since DNA ligase IV-deficient yeast are defective in their ability to carry out NHEJ. In S. cerevis iae, Sir2p, Sir3p and Sir4p, three proteins required for transcription al silencing, are also required for NHEJ. Additionally, the yeast muta nts, xrs2, rad50 and mre11, which are defective in meiotic recombinati on, are also defective in NHEJ. Here I review the evidence implicating these proteins as functioning in NHEJ and discuss their properties an d role in other pathways. The significance of DSB repair to clinical r adiosensitivity and human disorders is also evaluated. (C) 1998 by Rad iation Research Society.