Abstract
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.
Highlights
Homologous recombination (HR) is a key pathway in mammalian cells for the repair of several types of lesions, including DNA strand breaks
We find that mouse cells lacking this complex are sensitive to DNA damaging agents, in particular, those that cause breaks in DNA strands and that serve as cancer chemotherapeutics
These cells have increased numbers of chromosome aberrations when exposed to DNA damaging agents
Summary
Homologous recombination (HR) is a key pathway in mammalian cells for the repair of several types of lesions, including DNA strand breaks. A second key pathway for the repair of DSBs is nonhomologous end-joining (NHEJ), where two ends are joined with little or no sequence identity [6]. In addition to canonical two-ended DSBs, one-ended DSBs arise in DNA [7]. These lesions form when a replication fork encounters a DNA single-strand break that is not repaired by base excision repair, for example, from a covalent topoisomerase I-DNA intermediate as a result of exposure to camptothecin [8,9]. HR is the primary mechanism for the repair of one-ended DSBs, given that the joining of two unrelated one-ended DSBs by NHEJ would give rise to genomic rearrangements [7]
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