Avoidance of Ribonucleotide-induced Mutations by RNase H2 and Srs2-Exo1 Mechanisms

Overview

Journal Nature

Specialty Science

Date 2014 Jun 5

PMID 24896181

Citations 61

Authors

Catherine J Potenski

Hengyao Niu

Patrick Sung

Hannah L Klein

Affiliations

Soon will be listed here.

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.

Citing Articles

The separation pin distinguishes the pro- and anti-recombinogenic functions of Saccharomyces cerevisiae Srs2.

Meir A, Raina V, Rivera C, Marie L, Symington L, Greene E Nat Commun. 2023; 14(1):8144.

PMID: 38065943 PMC: 10709652. DOI: 10.1038/s41467-023-43918-4.

Molecular basis for processing of topoisomerase 1-triggered DNA damage by Apn2/APE2.

Williams J, Wojtaszek J, Appel D, Krahn J, Wallace B, Walsh E Cell Rep. 2022; 41(1):111448.

PMID: 36198268 PMC: 9732815. DOI: 10.1016/j.celrep.2022.111448.

Ribonucleotide Incorporation by Eukaryotic B-Family Replicases and Its Implications for Genome Stability.

Williams J, Kunkel T Annu Rev Biochem. 2022; 91:133-155.

PMID: 35287470 PMC: 9384702. DOI: 10.1146/annurev-biochem-032620-110354.

Signatures of TOP1 transcription-associated mutagenesis in cancer and germline.

Reijns M, Parry D, Williams T, Nadeu F, Hindshaw R, Rios Szwed D Nature. 2022; 602(7898):623-631.

PMID: 35140396 PMC: 8866115. DOI: 10.1038/s41586-022-04403-y.

Specific Human ATR and ATM Inhibitors Modulate Single Strand DNA Formation in Exposed to Oxidative Agent.

Bernardes da Silva R, Dos Reis Bertoldo W, Naves L, de Vito F, Dener Damasceno J, Tosi L Front Cell Infect Microbiol. 2022; 11:802613.

PMID: 35059327 PMC: 8763966. DOI: 10.3389/fcimb.2021.802613.

References

Van Komen S, Reddy M, Krejci L, Klein H, Sung P . ATPase and DNA helicase activities of the Saccharomyces cerevisiae anti-recombinase Srs2. J Biol Chem. 2003; 278(45):44331-7. DOI: 10.1074/jbc.M307256200. View

Lisby M, Rothstein R, Mortensen U . Rad52 forms DNA repair and recombination centers during S phase. Proc Natl Acad Sci U S A. 2001; 98(15):8276-82. PMC: 37432. DOI: 10.1073/pnas.121006298. View

Lujan S, Williams J, Clausen A, Clark A, Kunkel T . Ribonucleotides are signals for mismatch repair of leading-strand replication errors. Mol Cell. 2013; 50(3):437-43. PMC: 3658170. DOI: 10.1016/j.molcel.2013.03.017. View

Spell R, Jinks-Robertson S . Determination of mitotic recombination rates by fluctuation analysis in Saccharomyces cerevisiae. Methods Mol Biol. 2004; 262:3-12. DOI: 10.1385/1-59259-761-0:003. View

Scheller J, Schurer A, Rudolph C, Hettwer S, Kramer W . MPH1, a yeast gene encoding a DEAH protein, plays a role in protection of the genome from spontaneous and chemically induced damage. Genetics. 2000; 155(3):1069-81. PMC: 1461162. DOI: 10.1093/genetics/155.3.1069. View

Genschel J, Bazemore L, Modrich P . Human exonuclease I is required for 5' and 3' mismatch repair. J Biol Chem. 2002; 277(15):13302-11. DOI: 10.1074/jbc.M111854200. View

Nguyen L, Barsky D, Fernandes M, Wilson 3rd D . Molecular interactions of human Exo1 with DNA. Nucleic Acids Res. 2002; 30(4):942-9. PMC: 100345. DOI: 10.1093/nar/30.4.942. View

Krejci L, Macris M, Li Y, Van Komen S, Villemain J, Ellenberger T . Role of ATP hydrolysis in the antirecombinase function of Saccharomyces cerevisiae Srs2 protein. J Biol Chem. 2004; 279(22):23193-9. DOI: 10.1074/jbc.M402586200. View

Crow Y, Leitch A, Hayward B, Garner A, Parmar R, Griffith E . Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection. Nat Genet. 2006; 38(8):910-6. DOI: 10.1038/ng1842. View

10.

Chen C, Umezu K, Kolodner R . Chromosomal rearrangements occur in S. cerevisiae rfa1 mutator mutants due to mutagenic lesions processed by double-strand-break repair. Mol Cell. 1998; 2(1):9-22. DOI: 10.1016/s1097-2765(00)80109-4. View

11.

Burgess R, Lisby M, Altmannova V, Krejci L, Sung P, Rothstein R . Localization of recombination proteins and Srs2 reveals anti-recombinase function in vivo. J Cell Biol. 2009; 185(6):969-81. PMC: 2711611. DOI: 10.1083/jcb.200810055. View

12.

Chanet R, Heude M, Adjiri A, Maloisel L, Fabre F . Semidominant mutations in the yeast Rad51 protein and their relationships with the Srs2 helicase. Mol Cell Biol. 1996; 16(9):4782-9. PMC: 231479. DOI: 10.1128/MCB.16.9.4782. View

13.

Aguilera A, Klein H . Genetic control of intrachromosomal recombination in Saccharomyces cerevisiae. I. Isolation and genetic characterization of hyper-recombination mutations. Genetics. 1988; 119(4):779-90. PMC: 1203464. DOI: 10.1093/genetics/119.4.779. View

14.

Adkins N, Niu H, Sung P, Peterson C . Nucleosome dynamics regulates DNA processing. Nat Struct Mol Biol. 2013; 20(7):836-42. PMC: 3711194. DOI: 10.1038/nsmb.2585. View

15.

Ghodgaonkar M, Lazzaro F, Olivera-Pimentel M, Artola-Boran M, Cejka P, Reijns M . Ribonucleotides misincorporated into DNA act as strand-discrimination signals in eukaryotic mismatch repair. Mol Cell. 2013; 50(3):323-32. PMC: 3653069. DOI: 10.1016/j.molcel.2013.03.019. View

16.

Veaute X, Jeusset J, Soustelle C, Kowalczykowski S, Le Cam E, Fabre F . The Srs2 helicase prevents recombination by disrupting Rad51 nucleoprotein filaments. Nature. 2003; 423(6937):309-12. DOI: 10.1038/nature01585. View

17.

Nick McElhinny S, Kumar D, Clark A, Watt D, Watts B, Lundstrom E . Genome instability due to ribonucleotide incorporation into DNA. Nat Chem Biol. 2010; 6(10):774-81. PMC: 2942972. DOI: 10.1038/nchembio.424. View

18.

Cho J, Kim N, Li Y, Jinks-Robertson S . Two distinct mechanisms of Topoisomerase 1-dependent mutagenesis in yeast. DNA Repair (Amst). 2013; 12(3):205-11. PMC: 3594648. DOI: 10.1016/j.dnarep.2012.12.004. View

19.

Colavito S, Macris-Kiss M, Seong C, Gleeson O, Greene E, Klein H . Functional significance of the Rad51-Srs2 complex in Rad51 presynaptic filament disruption. Nucleic Acids Res. 2009; 37(20):6754-64. PMC: 2777448. DOI: 10.1093/nar/gkp748. View

20.

Fiorani S, Mimun G, Caleca L, Piccini D, Pellicioli A . Characterization of the activation domain of the Rad53 checkpoint kinase. Cell Cycle. 2008; 7(4):493-9. DOI: 10.4161/cc.7.4.5323. View