RNase H2 roles in genome integrity revealed by unlinking its activities
- PMID: 23355612
- PMCID: PMC3597693
- DOI: 10.1093/nar/gkt027
RNase H2 roles in genome integrity revealed by unlinking its activities
Abstract
Ribonuclease H2 (RNase H2) protects genome integrity by its dual roles of resolving transcription-related R-loops and ribonucleotides incorporated in DNA during replication. To unlink these two functions, we generated a Saccharomyces cerevisiae RNase H2 mutant that can resolve R-loops but cannot cleave single ribonucleotides in DNA. This mutant definitively correlates the 2-5 bp deletions observed in rnh201Δ strains with single rNMPs in DNA. It also establishes a connection between R-loops and Sgs1-mediated replication reinitiation at stalled forks and identifies R-loops uniquely processed by RNase H2. In mouse, deletion of any of the genes coding for RNase H2 results in embryonic lethality, and in humans, RNase H2 hypomorphic mutations cause Aicardi-Goutières syndrome (AGS), a neuroinflammatory disorder. To determine the contribution of R-loops and rNMP in DNA to the defects observed in AGS, we characterized in yeast an AGS-related mutation, which is impaired in processing both substrates, but has sufficient R-loop degradation activity to complement the defects of rnh201Δ sgs1Δ strains. However, this AGS-related mutation accumulates 2-5 bp deletions at a very similar rate as the deletion strain.
Figures
Similar articles
-
The structural and biochemical characterization of human RNase H2 complex reveals the molecular basis for substrate recognition and Aicardi-Goutières syndrome defects.J Biol Chem. 2011 Mar 25;286(12):10540-50. doi: 10.1074/jbc.M110.181974. Epub 2010 Dec 22. J Biol Chem. 2011. PMID: 21177858 Free PMC article.
-
Elevated Genome-Wide Instability in Yeast Mutants Lacking RNase H Activity.Genetics. 2015 Nov;201(3):963-75. doi: 10.1534/genetics.115.182725. Epub 2015 Sep 22. Genetics. 2015. PMID: 26400613 Free PMC article.
-
Two RNase H2 Mutants with Differential rNMP Processing Activity Reveal a Threshold of Ribonucleotide Tolerance for Embryonic Development.Cell Rep. 2018 Oct 30;25(5):1135-1145.e5. doi: 10.1016/j.celrep.2018.10.019. Cell Rep. 2018. PMID: 30380406 Free PMC article.
-
RNases H1 and H2: guardians of the stability of the nuclear genome when supply of dNTPs is limiting for DNA synthesis.Curr Genet. 2020 Dec;66(6):1073-1084. doi: 10.1007/s00294-020-01086-8. Epub 2020 Sep 4. Curr Genet. 2020. PMID: 32886170 Free PMC article. Review.
-
RNase H2-RED carpets the path to eukaryotic RNase H2 functions.DNA Repair (Amst). 2019 Dec;84:102736. doi: 10.1016/j.dnarep.2019.102736. Epub 2019 Oct 23. DNA Repair (Amst). 2019. PMID: 31761672 Free PMC article. Review.
Cited by
-
Structures of LIG1 uncover the mechanism of sugar discrimination against 5'-RNA-DNA junctions during ribonucleotide excision repair.J Biol Chem. 2024 Sep;300(9):107688. doi: 10.1016/j.jbc.2024.107688. Epub 2024 Aug 17. J Biol Chem. 2024. PMID: 39159820 Free PMC article.
-
RTF2 controls replication repriming and ribonucleotide excision at the replisome.Nat Commun. 2024 Mar 2;15(1):1943. doi: 10.1038/s41467-024-45947-z. Nat Commun. 2024. PMID: 38431617 Free PMC article.
-
Effective Antiviral Application of Antisense in Plants by Exploiting Accessible Sites in the Target RNA.Int J Mol Sci. 2023 Dec 5;24(24):17153. doi: 10.3390/ijms242417153. Int J Mol Sci. 2023. PMID: 38138982 Free PMC article.
-
Processing of matched and mismatched rNMPs in DNA by archaeal ribonucleotide excision repair.iScience. 2023 Nov 17;26(12):108479. doi: 10.1016/j.isci.2023.108479. eCollection 2023 Dec 15. iScience. 2023. PMID: 38077150 Free PMC article.
-
In Silico Characterization of RNASEH2A Pathogenic Variants and Identification of Novel Splice Site Donor Variant c.549+1G>T in Indian Population.Cureus. 2023 Jun 13;15(6):e40366. doi: 10.7759/cureus.40366. eCollection 2023 Jun. Cureus. 2023. PMID: 37456470 Free PMC article.
References
-
- Tadokoro T, Kanaya S. Ribonuclease H: molecular diversities, substrate binding domains, and catalytic mechanism of the prokaryotic enzymes. FEBS J. 2009;276:1482–1493. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases