Impairment of homologous recombination control in a Fanconi anemia-like Chinese hamster cell mutant.
DNA interstrand cross-links (ICL)-inducing agents such as cisplatin, mitomycin C (MMC) and nitrogen mustards are widely used as potent antitumor drugs. Although ICL repair mechanism is not yet well characterized in mammalian cells, this pathway is thought to involve a sequential action of nucleotide excision repair (NER) and homologous recombination (HR). The importance of unraveling ICL repair pathways is highlighted by the hypersensitivity to ICL-inducing agents in cells of patients with the genetic disease Fanconi anemia (FA) and in cells mutated in the Breast Cancer susceptibility genes BRCA1 and BRCA2. To better characterize the involvement of HR in the sensitivity to ICL-inducing agents, we examined spontaneous and ICL-induced HR in rodent FA-like V-H4 cells. In this report, we show that MMC-hypersensitive V-H4 cells exhibit an increased spontaneous homology-directed repair (HDR) activity compared to the resistant V79 parental cells. Elevated HDR activity results mainly in increased conservative Rad51-dependent recombination, without affecting non-conservative single-strand annealing process (SSA). We also show that HDR activity is enhanced following MMC treatment in parental cells, but not in rodent FA-like V-H4 cells. Moreover, our data indicate that Rad51 foci formation is significantly delayed in these FA-like cells in response to crosslinking agent. These findings provide evidence for an impairment of HR control in V-H4 cells and emphasize the involvement of the FA pathway in HR-mediated repair.
Larminat
Florence
F
Institut de Pharmacologie et de Biologie Structurale, UMR 5089, C.N.R.S., 205, Route de Narbonne, 31077 Toulouse Cedex 4, France. Florence.Larminat@cict.fr
Germanier
Maryse
M
Papouli
Efterpi
E
Defais
Martine
M
D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D051135:Rad51 Recombinase; D011995:Recombination, Genetic
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D051135:Rad51 Recombinase