NBS1 cooperates with homologous recombination to counteract chromosome breakage during replication

LJL Brugmans, Nicole Verkaik, MGS Kunen, E Drunen, BR Williams, JHJ Petrini, Roland Kanaar, J. Essers, Dik van Gent

Research output: Contribution to journalArticleAcademic

7 Citations (Scopus)

Abstract

Nijmegen breakage syndrome (NBS) is characterized by genome instability and cancer predisposition. NBS patients contain a mutation in the NBS1 gene, which encodes the NBS1 component of the DNA double-strand break (DSB) response complex MRE11/RAD50/NBS1. To investigate the NBS phenotype in more detail, we combined the mouse mimic of the most common patient mutation (Nbs1(Delta B/Delta B)) with a Rad54 null mutation, which diminishes homologous recombination. Double mutant cells were particularly sensitive to treatments that cause single strand breaks (SSBs), presumably because these SSBs can be converted into detrimental DSBs upon passage of a replication fork. The persistent presence of nuclear RAD51 foci and increased levels of chromatid type breaks in metaphase spreads indicated that replication-associated DSBs are repaired inefficiently in the double mutant cells. We conclude that Nbs1 and Rad54 function cooperatively, but in separate pathways to counteract this type of DNA damage and discuss mechanistic implications of these findings. (C) 2009 Elsevier B.V. All rights reserved.
Original languageUndefined/Unknown
Pages (from-to)1363-1370
Number of pages8
JournalDNA Repair
Volume8
Issue number12
DOIs
Publication statusPublished - 2009

Cite this