title: Two distinct mechanisms of Topoisomerase 1-dependent mutagenesis in yeast.
abstract: Topoisomerase 1 (Top1) resolves transcription-associated supercoils by generating transient single-strand breaks in DNA. Top1 activity in yeast is a major source of transcription-associated mutagenesis, generating a distinctive mutation signature characterized by deletions in short, tandem repeats. A similar signature is associated with the persistence of ribonucleoside monophosphates (rNMPs) in DNA, and it also depends on Top1 activity. There is only partial overlap, however, between Top1-dependent deletion hotspots identified in highly transcribed DNA and those associated with rNMPs, suggesting the existence of both rNMP-dependent and rNMP-independent events. Here, we present genetic studies confirming that there are two distinct types of hotspots. Data suggest a novel model in which rNMP-dependent hotspots are generated by sequential Top1 reactions and are consistent with rNMP-independent hotspots reflecting processing of a trapped Top1 cleavage complex.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA. jangeun.cho@duke.edu
authors.forename: Jang-Eun
authors.initials: JE
authors.lastname: Cho
authors.forename: Nayun
authors.initials: N
authors.lastname: Kim
authors.forename: Yue C
authors.initials: YC
authors.lastname: Li
authors.forename: Sue
authors.initials: S
authors.lastname: Jinks-Robertson
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D001483:Base Sequence; D002166:Camptothecin / Q000494:pharmacology; D004264:DNA Topoisomerases, Type I / Q000502:physiology*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D016914:Ribonuclease H / Q000235:genetics; D012265:Ribonucleotides / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D017384:Sequence Deletion; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D026923:Amino Acid Transport Systems, Basic; C502212:CAN1 protein, S cerevisiae; D012265:Ribonucleotides; D029701:Saccharomyces cerevisiae Proteins; D059004:Topoisomerase I Inhibitors; C091139:ribonuclease HII; D016914:Ribonuclease H; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin