Brc1-Mediated DNA Repair and Damage Tolerance

• Published in: Genetics (Austin) Vol. 171; no. 2; pp. 457 - 468
• Main Authors: Sheedy, Daniel M, Dimitrova, Dora, Rankin, Jessica K, Bass, Kirstin L, Lee, Karen M, Tapia-Alveal, Claudia, Harvey, Susan H, Murray, Johanne M, O'Connell, Matthew J
• Format: Journal Article
• Language: English
• Published: United States Genetics Soc America 01.10.2005; Genetics Society of America; Copyright © 2005 by the Genetics Society of America
• Subjects: Cell cycle; Cell Cycle Proteins - genetics; DNA damage; DNA Damage - genetics; DNA repair; DNA Repair - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endonucleases - genetics; Endonucleases - metabolism; Epistasis, Genetic; Genetics; Investigations; Metronidazole - analogs & derivatives; Metronidazole - toxicity; Proteins; Recombination, Genetic - genetics; Schizosaccharomyces - drug effects; Schizosaccharomyces - genetics; Schizosaccharomyces - radiation effects; Schizosaccharomyces pombe; Schizosaccharomyces pombe Proteins - genetics; Schizosaccharomyces pombe Proteins - metabolism; Ultraviolet Rays
• ISSN: 0016-6731; 1943-2631; 1943-2631
• DOI: 10.1534/genetics.105.044966

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.