NBS1 cooperates with homologous recombination to counteract chromosome breakage during replication Journal Article
| Authors: | Brugmans, L.; Verkaik, N. S.; Kunen, M.; van Drunen, E.; Williams, B. R.; Petrini, J. H. J.; Kanaar, R.; Essers, J.; van Gent, D. C. |
| Article Title: | NBS1 cooperates with homologous recombination to counteract chromosome breakage during replication |
| 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<sup>ΔB/ΔB</sup>) 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. © 2009 Elsevier B.V. |
| Keywords: | protein phosphorylation; gene mutation; nonhuman; dna replication; dna synthesis; animal cell; mouse; phenotype; animals; cell cycle proteins; mice; mre11 protein; rad50 protein; dna damage; homologous recombination; cells, cultured; cell cycle; cancer susceptibility; embryo; embryonic stem cell; camptothecin; cytogenetics; nibrin; dna strand breakage; nuclear proteins; chromosome aberration; dna; double stranded dna; recombination, genetic; western blotting; ionizing radiation; mitomycin c; cell cycle checkpoint; chromosomal instability; dna damage response; dna double-strand break repair; mre11/rad50/nbs1 complex; rad54; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; rad54 protein; gamma irradiation; nijmegen breakage syndrome; radiosensitivity; sister chromatid exchange; chromosome breakage |
| Journal Title: | DNA Repair |
| Volume: | 8 |
| Issue: | 12 |
| ISSN: | 1568-7864 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2009-12-03 |
| Start Page: | 1363 |
| End Page: | 1370 |
| Language: | English |
| DOI: | 10.1016/j.dnarep.2009.09.002 |
| PUBMED: | 19782649 |
| PROVIDER: | scopus |
| PMCID: | PMC2995292 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 30 November 2010" - "CODEN: DRNEA" - "Source: Scopus" |
