The nonhomologous DNA end joining pathway is important for chromosome stability in primary fibroblasts

There are two types of chromosome instability, structural and numerical, an d these are important in cancer. Many structural abnormalities are likely t o involve double-strand DNA (dsDNA) breaks. Nonhomologous DNA end joining ( NHEJ) and homologous recombination are the major pathways for repairing dsD NA breaks. NHU is the primary pathway for repairing dsDNA breaks throughout the G0, G1 and early S phases of the cell cycle [1], Ku86 and DNA ligase I V are two major proteins in the NHU pathway. We examined primary dermal fib roblasts from mice (wild type, Ku86(+/-), Ku86(-/-), and DNA ligase IV+/-) for chromosome breaks. Fibroblasts from Ku86(+/-) or DNA ligase IV+/- mice have elevated frequencies of chromosome breaks compared with those from wil d-type mice. Fibroblasts from Ku86(-/-) mice have even higher levels of chr omosome breaks. Primary pre-B cells from the same animals did not show sign ificant accumulation of chromosome breaks. Rather the pre-B cells showed in creased cell death. These studies demonstrate that chromosome breaks arise frequently and that NHU is required to repair this constant spontaneous dam age. (C) 1999 Elsevier Science Ltd. All rights reserved.