title: Mms22p protects Saccharomyces cerevisiae from DNA damage induced by topoisomerase II.
abstract: The cleavage reaction of topoisomerase II, which creates double-stranded DNA breaks, plays a central role in both the cure and initiation of cancer. Therefore, it is important to understand the cellular processes that repair topoisomerase II-generated DNA damage. Using a genome-wide approach with Saccharomyces cerevisiae, we found that Deltamre11, Deltaxrs2, Deltarad50, Deltarad51, Deltarad52, Deltarad54, Deltarad55, Deltarad57 and Deltamms22 strains were hypersensitive to etoposide, a drug that specifically increases levels of topoisomerase II-mediated DNA breaks. These results confirm that the single-strand invasion pathway of homologous recombination is the major pathway that repairs topoisomerase II-induced DNA damage in yeast and also indicate an important role for Mms22p. Although Deltamms22 strains are sensitive to several DNA-damaging agents, little is known about the function of Mms22p. Deltamms22 cultures accumulate in G2/M, and display an abnormal cell cycle response to topoisomerase II-mediated DNA damage. MMS22 appears to function outside of the single-strand invasion pathway, but levels of etoposide-induced homologous recombination in Deltamms22 cells are lower than wild-type. MMS22 is epistatic with RTT101 and RTT107, genes that encode its protein binding partners. Finally, consistent with a role in DNA processes, Mms22p localizes to discrete nuclear foci, even in the absence of etoposide or its binding partners.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine Nashville, TN 37232-0146, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Baldwin
authors.forename: A C
authors.initials: AC
authors.lastname: Berger
authors.forename: A H
authors.initials: AH
authors.lastname: Corbett
authors.forename: N
authors.initials: N
authors.lastname: Osheroff
mesh_terms: D002453:Cell Cycle; D002467:Cell Nucleus / Q000737:chemistry; D044842:Cullin Proteins / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D005047:Etoposide / Q000633:toxicity; D017353:Gene Deletion; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*
chemical_list: D044842:Cullin Proteins; C497133:Mms22 protein, S cerevisiae; C476451:RTT101 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D005047:Etoposide; D004250:DNA Topoisomerases, Type II
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