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Originally published as Genetics Published Articles Ahead of Print on June 21, 2005.

Genetics, Vol. 171, 457-468, October 2005, Copyright © 2005
doi:10.1534/genetics.105.044966

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Brc1-Mediated DNA Repair and Damage Tolerance

Daniel M. Sheedy*,{dagger}, Dora Dimitrova*, Jessica K. Rankin*, Kirstin L. Bass*, Karen M. Lee*, Claudia Tapia-Alveal*, Susan H. Harvey*,{dagger}, Johanne M. Murray{ddagger} and Matthew J. O'Connell*,{dagger},1

* Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, {dagger} Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, Melbourne, Victoria 8006, Australia and {ddagger} Genome Damage and Stability Centre, School of Biological Science, University of Sussex, Falmer, Brighton BN1 9RQ, United Kingdom

1 Corresponding author: Department of Oncological Sciences, Mount Sinai School of Medicine, 1425 Madison Ave., Room 15-70, New York, NY 10029.
E-mail: matthew.oconnell{at}mssm.edu

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 brc1{Delta} 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 brc1{Delta} 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.




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