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

Nature Structural & Molecular Biology
Jessica S WilliamsThomas A Kunkel

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) ɛ, 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 ɛ 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.

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Citations

Jan 30, 2016·Critical Reviews in Biochemistry and Molecular Biology·Scott A LujanThomas A Kunkel
Mar 22, 2016·Trends in Biochemical Sciences·Susana M Cerritelli, Robert J Crouch
Apr 21, 2016·Nature Reviews. Molecular Cell Biology·Jessica S WilliamsThomas A Kunkel
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Mar 7, 2020·International Journal of Molecular Sciences·Giulia Maria NavaFederico Lazzaro
Aug 23, 2019·DNA Repair·Karin C NitissLeslyn A Hanakahi
Jan 20, 2021·Critical Reviews in Biochemistry and Molecular Biology·Zhi-Xiong ZhouThomas A Kunkel
Nov 26, 2019·DNA Repair·Susana M Cerritelli, Robert J Crouch
Jan 22, 2021·Nature Communications·Jessica S WilliamsThomas A Kunkel

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