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doi:10.1534/genetics.106.057836
A more recent version of this article appeared on December 1, 2006.
REGULAR RESEARCH PAPERS |
The F-box protein Dia2 overcomes replication impedance to promote genome stability in Saccharomyces cerevisiae
Deborah Blake 1, Brian Luke 2, Pamela Kanellis 1, Paul Jorgensen 3, Theo Goh 4, Sonya Penfold 5, Bobby-Joe Breitkreutz 1, Daniel Durocher 1, Matthias Peter 6 and Mike Tyers 1*
1 Samuel Lunenfeld Research Institute
2 ISREC
3 Harvard Medical School
4 Campbell Family Institute for Breast Cancer Research
5 Blake, Cassels & Graydon LLP
6 ETH Zurich
* To whom correspondence should be addressed. E-mail: tyers{at}mshri.on.ca.
Submitted on March 5, 2006
Revised on April 5, 2006
Accepted on 23 May 2006
The maintenance of DNA replication fork stability under conditions of DNA damage and at natural replication pause sites is essential for genome stability. Here, we describe a novel role for the F-box protein Dia2 in promoting genome stability in the budding yeast Saccharomyces cerevisiae. Like most other F-box proteins, Dia2 forms an SCF (Skp1-Cdc53/Cullin-F-box) E3 ubiquitin ligase complex. Systematic analysis of genetic interactions between dia2
and ~4,400 viable gene deletion mutants revealed synthetic lethal/synthetic sick interactions with a broad spectrum of DNA replication, recombination, checkpoint, and chromatin remodeling pathways. dia2 strains exhibit constitutive activation of the checkpoint kinase Rad53 and elevated counts of endogenous DNA repair foci, and are unable to overcome MMS-induced replicative stress. Notably, dia2 strains display a high rate of gross chromosomal rearrangements (GCRs) that involve the rDNA locus and an increase in extra-chromosomal rDNA circle (ERC) formation, consistent with an observed enrichment of Dia2 in the nucleolus. These results suggest that Dia2 is essential for stable passage of replication forks through regions of damaged DNA and natural fragile regions, particularly the replication fork barrier (RFB) of rDNA repeat loci. We propose that the SCFDia2 ubiquitin ligase serves to modify or degrade protein substrates that would otherwise impede the replication fork in problematic regions of the genome.
Key Words: DNA damage, SCF ubiquitin ligase, chromosome loss, rDNA, synthetic genetic array
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