Role for the mammalian Swi5-Sfr1 complex in DNA strand break repair through homologous recombination.
In fission yeast, the Swi5-Sfr1 complex plays an important role in homologous recombination (HR), a pathway crucial for the maintenance of genomic integrity. Here we identify and characterize mammalian Swi5 and Sfr1 homologues. Mouse Swi5 and Sfr1 are nuclear proteins that form a complex in vivo and in vitro. Swi5 interacts in vitro with Rad51, the DNA strand-exchange protein which functions during HR. By generating Swi5(-/-) and Sfr1(-/-) embryonic stem cell lines, we found that both proteins are mutually interdependent for their stability. Importantly, the Swi5-Sfr1 complex plays a role in HR when Rad51 function is perturbed in vivo by expression of a BRC peptide from BRCA2. Swi5(-/-) and Sfr1(-/-) cells are selectively sensitive to agents that cause DNA strand breaks, in particular ionizing radiation, camptothecin, and the Parp inhibitor olaparib. Consistent with a role in HR, sister chromatid exchange induced by Parp inhibition is attenuated in Swi5(-/-) and Sfr1(-/-) cells, and chromosome aberrations are increased. Thus, Swi5-Sfr1 is a newly identified complex required for genomic integrity in mammalian cells with a specific role in the repair of DNA strand breaks.
Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Yufuko
Y
Akamatsu
Maria
M
Jasin
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D017386:Sequence Homology, Amino Acid; D020798:Two-Hybrid System Techniques
D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010793:Phthalazines; D010879:Piperazines; C556302:Sfr1 protein, mouse; C556301:Swi5 protein, mouse; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; C531550:olaparib; D002166:Camptothecin