Evidence that processing of ribonucleotides in DNA by topoisomerase 1 is leading-strand specific

Jessica S. Williams, Anders R. Clausen, Scott A. Lujan, Lisette Marjavaara, Alan B. Clark, Peter M. Burgers, Andrei Chabes, Thomas A. Kunkel

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Ribonucleotides incorporated during DNA replication are removed by RNase H2-dependent ribonucleotide excision repair (RER). In RER-defective yeast, topoisomerase 1 (Top1) incises DNA at unrepaired ribonucleotides, initiating their removal, but this is accompanied by RNA-DNA-damage phenotypes. Here we show that these phenotypes are incurred by a high level of ribonucleotides incorporated by a leading strand-replicase variant, DNA polymerase (Pol) ε, but not by orthologous variants of the lagging-strand replicases, Pols α or δ. Moreover, loss of both RNases H1 and H2 is lethal in combination with increased ribonucleotide incorporation by Pol ε but not by Pols α or δ. Several explanations for this asymmetry are considered, including the idea that Top1 incision at ribonucleotides relieves torsional stress in the nascent leading strand but not in the nascent lagging strand, in which preexisting nicks prevent the accumulation of superhelical tension.

Original languageEnglish
Pages (from-to)291-297
Number of pages7
JournalNature Structural and Molecular Biology
Volume22
Issue number4
DOIs
StatePublished - Apr 7 2015

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    Williams, J. S., Clausen, A. R., Lujan, S. A., Marjavaara, L., Clark, A. B., Burgers, P. M., Chabes, A., & Kunkel, T. A. (2015). Evidence that processing of ribonucleotides in DNA by topoisomerase 1 is leading-strand specific. Nature Structural and Molecular Biology, 22(4), 291-297. https://doi.org/10.1038/nsmb.2989