The role of RNase H2 in processing ribonucleotides incorporated during DNA replication

Williams, Jessica S.; Gehle, Daniel B.; Kunkel, Thomas A.

doi:10.1016/j.dnarep.2017.02.016

Cited by 19 publications

(16 citation statements)

References 41 publications

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“…In its absence, DNA molecules are released from stalled replication forks and can form duplexes in the cytosol that activate cGAS . RNAseH2 is another protein involved in DNA repair, and its absence leads to genome instability through a failure to remove incorporated ribonucleotides . DNA that fails to segregate properly during mitosis due to loss of RNAseH2 or other sources of damage can lead to the formation of micronuclei.…”

Section: Basic Biology Of the Sting Pathwaymentioning

confidence: 99%

STING pathway agonism as a cancer therapeutic

Flood

Higgs

et al. 2019

Immunological Reviews

235

183

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The fact that a subset of human cancers showed evidence for a spontaneous adaptive immune response as reflected by the T cell‐inflamed tumor microenvironment phenotype led to the search for candidate innate immune pathways that might be driving such endogenous responses. Preclinical studies indicated a major role for the host STING pathway, a cytosolic DNA sensing pathway, as a proximal event required for optimal type I interferon production, dendritic cell activation, and priming of CD8+ T cells against tumor‐associated antigens. STING agonists are therefore being developed as a novel cancer therapeutic, and a greater understanding of STING pathway regulation is leading to a broadened list of candidate immune regulatory targets. Early phase clinical trials of intratumoral STING agonists are already showing promise, alone and in combination with checkpoint blockade. Further advancement will derive from a deeper understanding of STING pathway biology as well as mechanisms of response vs resistance in individual cancer patients.

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Section: Basic Biology Of the Sting Pathwaymentioning

confidence: 99%

STING pathway agonism as a cancer therapeutic

Flood

Higgs

et al. 2019

Immunological Reviews

235

183

View full text Add to dashboard Cite

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“…For example, 2–5 bp deletions accumulate at low complexity regions in RNase H2 mutants [6]. This phenotype stems from a defect in normal RER initiation, which then affords an opportunity for mutagenic processing by topoisomerase 1 at regions containing rNMPs [7–11]. In addition to nucleotide-level mutations, the absence of RNase H2 has also been shown to destabilize chromosome structure, leading to increased rates of gene conversion, gene duplication, chromosomal rearrangements, chromosome loss, and loss-of-heterozygosity (LOH) [12–18].…”

Section: Introductionmentioning

confidence: 99%

Both R-loop removal and ribonucleotide excision repair activities of RNase H2 contribute substantially to chromosome stability

et al. 2017

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Cells carrying deletions of genes encoding H-class ribonucleases display elevated rates of chromosome instability. The role of these enzymes is to remove RNA-DNA associations including persistent mRNA-DNA hybrids (R-loops) formed during transcription, and ribonucleotides incorporated into DNA during replication. RNases H1 and H2 can degrade the RNA component of R-loops, but only RNase H2 can initiate accurate ribonucleotide excision repair (RER). In order to examine the specific contributions of these activities to chromosome stability, we measured rates of loss-of-heterozygosity (LOH) in diploid Saccharomyces cerevisiae yeast strains carrying the rnh201-RED separation-of-function allele, encoding a version of RNase H2 that is RER-defective, but partly retains its other activity. The LOH rate in rnh201-RED was intermediate between RNH201 and rnh201Δ. In strains carrying a mutant version of DNA polymerase ε (pol2-M644G) that incorporates more ribonucleotides than normal, the LOH rate in rnh201-RED was as high as the rate measured in rnh201Δ. Topoisomerase 1 cleavage at sites of ribonucleotide incorporation has been recently shown to produce DNA double strand breaks. Accordingly, in both the POL2 and pol2-M644G backgrounds, the LOH elevation in rnh201-RED was suppressed by top1Δ. In contrast, in strains that incorporate fewer ribonucleotides (pol2-M644L) the LOH rate in rnh201-RED was low and independent of topoisomerase 1. These results suggest that both R-loop removal and RER contribute substantially to chromosome stability, and that their relative contributions may be variable across different regions of the genome. In this scenario, a prominent contribution of R-loop removal may be expected at highly transcribed regions, whereas RER may play a greater role at hotspots of ribonucleotide incorporation.

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“…In yeast, the absence of RNase H2 increases spontaneous mutation rates as well as gene conversion events (Huang et al, 2003;Ii et al, 2011). This mutational signature is generated by Top1 incision at rNMPs followed by faulty Top1dependent alignment of the nicked DNA strand and religation (see above) (Kim et al, 2011;Williams et al, 2017). The most characteristic type of mutation upon loss of RER manifests in short deletions in repetitive sequences, mostly between two and five basepairs in length (Nick McElhinny et al, 2010a).…”

Section: Unrepaired Rnmps Affect Genome Stabilitymentioning

confidence: 99%

Molecular and physiological consequences of faulty eukaryotic ribonucleotide excision repair

Kellner

Luke

2019

The EMBO Journal

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The duplication of the eukaryotic genome is an intricate process that has to be tightly safe-guarded. One of the most frequently occurring errors during DNA synthesis is the mis-insertion of a ribonucleotide instead of a deoxyribonucleotide. Ribonucleotide excision repair (RER) is initiated by RNase H2 and results in errorfree removal of such mis-incorporated ribonucleotides. If left unrepaired, DNA-embedded ribonucleotides result in a variety of alterations within chromosomal DNA, which ultimately lead to genome instability. Here, we review how genomic ribonucleotides lead to chromosomal aberrations and discuss how the tight regulation of RER timing may be important for preventing unwanted DNA damage. We describe the structural impact of unrepaired ribonucleotides on DNA and chromatin and comment on the potential consequences for cellular fitness. In the context of the molecular mechanisms associated with faulty RER, we have placed an emphasis on how and why increased levels of genomic ribonucleotides are associated with severe autoimmune syndromes, neuropathology, and cancer. In addition, we discuss therapeutic directions that could be followed for pathologies associated with defective removal of ribonucleotides from doublestranded DNA.

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The role of RNase H2 in processing ribonucleotides incorporated during DNA replication

Cited by 19 publications

References 41 publications

STING pathway agonism as a cancer therapeutic

STING pathway agonism as a cancer therapeutic

Both R-loop removal and ribonucleotide excision repair activities of RNase H2 contribute substantially to chromosome stability

Molecular and physiological consequences of faulty eukaryotic ribonucleotide excision repair

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