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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 a Skp1-Cdc53\/Cullin-F-box (SCF) E3 ubiquitin\u2013ligase complex. Systematic analysis of genetic interactions between dia2\u0394 and \u223c4400 viable gene deletion mutants revealed synthetic lethal\/synthetic sick interactions with a broad spectrum of DNA replication, recombination, checkpoint, and chromatin-remodeling pathways. dia2\u0394 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\u0394 strains display a high rate of gross chromosomal rearrangements (GCRs) that involve the rDNA locus and an increase in extrachromosomal 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.<\/jats:p>","DOI":"10.1534\/genetics.106.057836","type":"journal-article","created":{"date-parts":[[2006,6,5]],"date-time":"2006-06-05T00:26:55Z","timestamp":1149467215000},"page":"1709-1727","source":"Crossref","is-referenced-by-count":57,"title":["The F-Box Protein Dia2 Overcomes Replication Impedance to Promote Genome Stability in <i>Saccharomyces cerevisiae<\/i>"],"prefix":"10.1093","volume":"174","author":[{"given":"Deborah","family":"Blake","sequence":"first","affiliation":[{"name":"Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada"},{"name":"Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Luke","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, 8093 Zu\u0308rich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Kanellis","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada"},{"name":"Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Jorgensen","sequence":"additional","affiliation":[{"name":"Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theo","family":"Goh","sequence":"additional","affiliation":[{"name":"Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya","family":"Penfold","sequence":"additional","affiliation":[{"name":"Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bobby-Joe","family":"Breitkreutz","sequence":"additional","affiliation":[{"name":"Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Durocher","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada"},{"name":"Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Peter","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, 8093 Zu\u0308rich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Tyers","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada"},{"name":"Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2006,12,1]]},"reference":[{"key":"2022010919583662200_BIB1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1101\/gad.1392506","volume":"20","year":"2006","journal-title":"Genes Dev."},{"key":"2022010919583662200_BIB2","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/emboj\/21.3.195","volume":"21","year":"2002","journal-title":"EMBO J."},{"key":"2022010919583662200_BIB3","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/ncb1101-958","volume":"3","year":"2001","journal-title":"Nat. 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