Avoidance of ribonucleotide-induced mutations by RNase H2 and Srs2-Exo1 mechanisms

Nature. 2014 Jul 10;511(7508):251-4. doi: 10.1038/nature13292. Epub 2014 Jun 1.

Abstract

Srs2 helicase is known to dismantle nucleofilaments of Rad51 recombinase to prevent spurious recombination events and unwind trinucleotide sequences that are prone to hairpin formation. Here we document a new, unexpected genome maintenance role of Srs2 in the suppression of mutations arising from mis-insertion of ribonucleoside monophosphates during DNA replication. In cells lacking RNase H2, Srs2 unwinds DNA from the 5' side of a nick generated by DNA topoisomerase I at a ribonucleoside monophosphate residue. In addition, Srs2 interacts with and enhances the activity of the nuclease Exo1, to generate a DNA gap in preparation for repair. Srs2-Exo1 thus functions in a new pathway of nick processing-gap filling that mediates tolerance of ribonucleoside monophosphates in the genome. Our results have implications for understanding the basis of Aicardi-Goutières syndrome, which stems from inactivation of the human RNase H2 complex.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • DNA Damage / genetics
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • Escherichia coli / genetics
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / metabolism*
  • Genomic Instability / genetics*
  • Mutation / genetics*
  • Ribonuclease H / metabolism*
  • Ribonucleotides / metabolism*
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • Ribonucleotides
  • Saccharomyces cerevisiae Proteins
  • SRS2 protein, S cerevisiae
  • Exodeoxyribonucleases
  • exodeoxyribonuclease I
  • ribonuclease HII
  • Ribonuclease H
  • DNA Helicases