Avoidance of rNMP-induced mutations via RNaseH2 and Srs2-Exo1 dependent mechanisms

Srs2 helicase is known to dismantle nucleofilaments of the Rad51 recombinase to prevent spurious recombination events(1–3, 4, 5, 6) and unwind trinucleotide sequences that are prone to hairpin formation(7). Here we document a new, unexpected genome maintenance role of Srs2 in the suppression of mutations arising from misinsertion of rNMPs during DNA replication. In cells lacking RNaseH2, Srs2 unwinds DNA from the 5′ side of a nick generated by DNA topoisomerase I(8) at a rNMP 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 novel pathway of nick processing-gap filling that mediates tolerance of rNMPs in the genome. Our results have implications for understanding the basis of Aicardi-Goutieres Syndrome, which stems from inactivation of the human RNaseH2 complex(9).