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DNA Repair (Amst). 2013 Mar 1;12(3):205-11. doi: 10.1016/j.dnarep.2012.12.004. Epub 2013 Jan 8.

Two distinct mechanisms of Topoisomerase 1-dependent mutagenesis in yeast.

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  • 1Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA. jangeun.cho@duke.edu

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.

Copyright © 2012 Elsevier B.V. All rights reserved.

PMID:
23305949
[PubMed - indexed for MEDLINE]
PMCID:
PMC3594648
Free PMC Article
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