RNase H2-RED Carpets the Path to Eukaryotic RNase H2 Functions

Overview

Journal DNA Repair (Amst)

Publisher Elsevier

Specialties Biochemistry
Molecular Biology

Date 2019 Nov 26

PMID 31761672

Citations 12

Authors

Susana M Cerritelli

Robert J Crouch

Affiliations

Soon will be listed here.

Abstract

Eukaryotic RNases H2 have dual functions in initiating the removal of ribonucleoside monophosphates (rNMPs) incorporated by DNA polymerases during DNA synthesis and in cleaving the RNA moiety of RNA/DNA hybrids formed during transcription and retrotransposition. The other major cellular RNase H, RNase H1, shares the hybrid processing activity, but not all substrates. After RNase H2 incision at the rNMPs in DNA the Ribonucleotide Excision Repair (RER) pathway completes the removal, restoring dsDNA. The development of the RNase H2-RED (Ribonucleotide Excision Defective) mutant enzyme, which can process RNA/DNA hybrids but is unable to cleave rNMPs embedded in DNA has unlinked the two activities and illuminated the roles of RNase H2 in cellular metabolism. Studies mostly in Saccharomyces cerevisiae, have shown both activities of RNase H2 are necessary to maintain genome integrity and that RNase H1 and H2 have overlapping as well as distinct RNA/DNA hybrid substrates. In mouse RNase H2-RED confirmed that rNMPs in DNA during embryogenesis induce lethality in a p53-dependent DNA damage response. In mammalian cell cultures, RNase H2-RED helped identifying DNA lesions produced by Top1 cleavage at rNMPs and led to determine that RNase H2 participates in the retrotransposition of LINE-1 elements. In this review, we summarize the studies and conclusions reached by utilization of RNase H2-RED enzyme in different model systems.

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References

Bartsch K, Knittler K, Borowski C, Rudnik S, Damme M, Aden K . Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy. Hum Mol Genet. 2017; 26(20):3960-3972. DOI: 10.1093/hmg/ddx283. View

Stetson D, Ko J, Heidmann T, Medzhitov R . Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell. 2008; 134(4):587-98. PMC: 2626626. DOI: 10.1016/j.cell.2008.06.032. View

Geronimo C, Zakian V . Getting it done at the ends: Pif1 family DNA helicases and telomeres. DNA Repair (Amst). 2016; 44:151-158. PMC: 5441554. DOI: 10.1016/j.dnarep.2016.05.021. View

Kojima Y, Tam O, Tam P . Timing of developmental events in the early mouse embryo. Semin Cell Dev Biol. 2014; 34:65-75. DOI: 10.1016/j.semcdb.2014.06.010. View

Ohtani N, Yanagawa H, Tomita M, Itaya M . Identification of the first archaeal Type 1 RNase H gene from Halobacterium sp. NRC-1: archaeal RNase HI can cleave an RNA-DNA junction. Biochem J. 2004; 381(Pt 3):795-802. PMC: 1133889. DOI: 10.1042/BJ20040153. View

Tadokoro T, Kanaya S . Ribonuclease H: molecular diversities, substrate binding domains, and catalytic mechanism of the prokaryotic enzymes. FEBS J. 2009; 276(6):1482-93. DOI: 10.1111/j.1742-4658.2009.06907.x. View

Lord C, Ashworth A . PARP inhibitors: Synthetic lethality in the clinic. Science. 2017; 355(6330):1152-1158. PMC: 6175050. DOI: 10.1126/science.aam7344. View

Uehara R, Cerritelli S, Hasin N, Sakhuja K, London M, Iranzo J . Two RNase H2 Mutants with Differential rNMP Processing Activity Reveal a Threshold of Ribonucleotide Tolerance for Embryonic Development. Cell Rep. 2018; 25(5):1135-1145.e5. PMC: 6309994. DOI: 10.1016/j.celrep.2018.10.019. View

Potenski C, Klein H . How the misincorporation of ribonucleotides into genomic DNA can be both harmful and helpful to cells. Nucleic Acids Res. 2014; 42(16):10226-34. PMC: 4176331. DOI: 10.1093/nar/gku773. View

10.

Yang W . Surviving the sun: repair and bypass of DNA UV lesions. Protein Sci. 2011; 20(11):1781-9. PMC: 3267942. DOI: 10.1002/pro.723. View

11.

Chon H, Matsumura H, Koga Y, Takano K, Kanaya S . Crystal structure and structure-based mutational analyses of RNase HIII from Bacillus stearothermophilus: a new type 2 RNase H with TBP-like substrate-binding domain at the N terminus. J Mol Biol. 2005; 356(1):165-78. DOI: 10.1016/j.jmb.2005.11.017. View

12.

Maul R, Chon H, Sakhuja K, Cerritelli S, Gugliotti L, Gearhart P . R-Loop Depletion by Over-expressed RNase H1 in Mouse B Cells Increases Activation-Induced Deaminase Access to the Transcribed Strand without Altering Frequency of Isotype Switching. J Mol Biol. 2017; 429(21):3255-3263. PMC: 5500445. DOI: 10.1016/j.jmb.2016.12.020. View

13.

Goodman M, Woodgate R . Translesion DNA polymerases. Cold Spring Harb Perspect Biol. 2013; 5(10):a010363. PMC: 3783050. DOI: 10.1101/cshperspect.a010363. View

14.

Figiel M, Nowotny M . Crystal structure of RNase H3-substrate complex reveals parallel evolution of RNA/DNA hybrid recognition. Nucleic Acids Res. 2014; 42(14):9285-94. PMC: 4132731. DOI: 10.1093/nar/gku615. View

15.

Yang W, Woodgate R . What a difference a decade makes: insights into translesion DNA synthesis. Proc Natl Acad Sci U S A. 2007; 104(40):15591-8. PMC: 2000391. DOI: 10.1073/pnas.0704219104. View

16.

Kreisel K, Engqvist M, Kalm J, Thompson L, Bostrom M, Navarrete C . DNA polymerase η contributes to genome-wide lagging strand synthesis. Nucleic Acids Res. 2019; 47(5):2425-2435. PMC: 6411934. DOI: 10.1093/nar/gky1291. View

17.

Nick McElhinny S, Gordenin D, Stith C, Burgers P, Kunkel T . Division of labor at the eukaryotic replication fork. Mol Cell. 2008; 30(2):137-44. PMC: 2654179. DOI: 10.1016/j.molcel.2008.02.022. View

18.

Conover H, Lujan S, Chapman M, Cornelio D, Sharif R, Williams J . Stimulation of Chromosomal Rearrangements by Ribonucleotides. Genetics. 2015; 201(3):951-61. PMC: 4649663. DOI: 10.1534/genetics.115.181149. View

19.

Wang C, Wang G, Feng X, Shepherd P, Zhang J, Tang M . Genome-wide CRISPR screens reveal synthetic lethality of RNASEH2 deficiency and ATR inhibition. Oncogene. 2018; 38(14):2451-2463. PMC: 6450769. DOI: 10.1038/s41388-018-0606-4. View

20.

Skourti-Stathaki K, Proudfoot N . A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression. Genes Dev. 2014; 28(13):1384-96. PMC: 4083084. DOI: 10.1101/gad.242990.114. View