NBS1 cooperates with homologous recombination to counteract chromosome breakage during replication.
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/DeltaB)) 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.
Department of Cell Biology & Genetics, Cancer Genomics Center, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
Linda
L
Brugmans
Nicole S
NS
Verkaik
Maurice
M
Kunen
Ellen
E
van Drunen
Bret R
BR
Williams
John H J
JH
Petrini
Roland
R
Kanaar
Jeroen
J
Essers
Dik C
DC
van Gent
D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019457:Chromosome Breakage; D004247:DNA / Q000235:genetics*; D004249:DNA Damage; D004265:DNA Helicases; D004261:DNA Replication; D004268:DNA-Binding Proteins; D005260:Female; D051379:Mice; D049932:Nijmegen Breakage Syndrome / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D004247:DNA; D004265:DNA Helicases; C103534:Rad54l protein, mouse