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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
Brc1-Mediated DNA Repair and Damage Tolerance
Daniel M. Sheedy*,
,
Dora Dimitrova*,
Jessica K. Rankin*,
Kirstin L. Bass*,
Karen M. Lee*,
Claudia Tapia-Alveal*,
Susan H. Harvey*,,
Johanne M. Murray
and
Matthew J. O'Connell*,,1
* Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, Melbourne, Victoria 8006, Australia and 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
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 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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