Brc1-mediated DNA repair and damage tolerance.
The structural maintenance of chromosome (SMC) proteins are key elements in controlling chromosome dynamics. In eukaryotic cells, three essential SMC complexes have been defined: cohesin, condensin, and the Smc5/6 complex. The latter is essential for DNA damage responses; in its absence both repair and checkpoint responses fail. In fission yeast, the UV-C and ionizing radiation (IR) sensitivity of a specific hypomorphic allele encoding the Smc6 subunit, rad18-74 (renamed smc6-74), is suppressed by mild overexpression of a six-BRCT-domain protein, Brc1. Deletion of brc1 does not result in a hypersensitivity to UV-C or IR, and thus the function of Brc1 relative to the Smc5/6 complex has remained unclear. Here we show that brc1Delta cells are hypersensitive to a range of radiomimetic drugs that share the feature of creating lesions that are an impediment to the completion of DNA replication. Through a genetic analysis of brc1Delta epistasis and by defining genes required for Brc1 to suppress smc6-74, we find that Brc1 functions to promote recombination through a novel postreplication repair pathway and the structure-specific nucleases Slx1 and Mus81. Activation of this pathway through overproduction of Brc1 bypasses a repair defect in smc6-74, reestablishing resolution of lesions by recombination.
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
Daniel M
DM
Sheedy
Dora
D
Dimitrova
Jessica K
JK
Rankin
Kirstin L
KL
Bass
Karen M
KM
Lee
Claudia
C
Tapia-Alveal
Susan H
SH
Harvey
Johanne M
JM
Murray
Matthew J
MJ
O'Connell
D018797:Cell Cycle Proteins / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D004843:Epistasis, Genetic; D008795:Metronidazole / Q000031:analogs & derivatives / Q000633:toxicity; D011995:Recombination, Genetic / Q000235:genetics*; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics* / Q000378:metabolism*; D014466:Ultraviolet Rays
C511286:Brc1 protein, S pombe; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C495865:MUS81 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; C486630:smc6 protein, S pombe; C051964:metronidazole monosuccinate; D008795:Metronidazole; D004720:Endonucleases