RNase H eliminates R‐loops that disrupt DNA replication but is nonessential for efficient DSB repair

Zhao, Hongchang; Zhu, Min; Limbo, Oliver; Russell, Paul

doi:10.15252/embr.201745335

Cited by 68 publications

(56 citation statements)

References 68 publications

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“…The exact mechanism by which these proteins function is not fully understood; however, it is becoming clear that they are acting upon RNA molecules at break sites. There is substantial evidence implicating RNA molecules in DNA repair, and several publications have now corroborated the generation of DNA:RNA hybrids (R-loops) at DSBs and importantly demonstrated that these structures are required for efficient DSB repair [18][19][20][21][22][23][24][25][26][27][28] . Interestingly, many RBPs are implicated to function via these DSB-induced Rloops, for example, Drosha has been shown to be required for their generation and RNase H2 and Senataxin for their resolution 19,21,24 .…”

Section: Introductionmentioning

confidence: 99%

DNA:RNA hybrids form at DNA double-strand breaks in transcriptionally active loci

Bader

Bushell

2020

Cell Death Dis

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The recent discovery of DNA:RNA hybrids, or R-loops, actively forming at DNA double-strand breaks (DSBs) has unlocked fresh insight into how RNA participates in DNA repair. However, the manner of DSB-induced R-loop formation is vital in determining its mechanism of action and is currently under debate. Here, we analyse published DNA:RNA-hybrid sequencing to elucidate the features that determine DSB-induced R-loop formation. We found that pre-existing transcriptional activity was critical for R-loop generation at break sites, suggesting that these RNAs are transcribed prior to break induction. In addition, this appeared to be a specific DSB response at the break, distinct from traditional, co-transcriptionally formed R-loops. We hypothesise that R-loop formation is orchestrated by the damage response at transcriptionally active DSB loci to specifically maintain these genomic regions. Further investigation is required to fully understand how canonical repair processes regulate R-loops at breaks and how they participate in the repair process.

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Section: Introductionmentioning

confidence: 99%

DNA:RNA hybrids form at DNA double-strand breaks in transcriptionally active loci

Bader

Bushell

2020

Cell Death Dis

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“…Perhaps even more important is the fact that the system produces one-ended DSBs which more accurately resemble the type of substrates resulting from collapsed replication forks [136]. Using wild type cells or several mating type defective mutants ( Figure 5B) [130,137,138] the role of various DNA damage response genes have been investigated [136,139,140]. Work has also led to the identification of several recombination and replication genes, particularly the swi (switching) genes [117,118,141,142].…”

Section: Mating Type Loci Serve As a Natural Site For Studying Collapmentioning

confidence: 99%

Schizosaccharomyces pombe Assays to Study Mitotic Recombination Outcomes

Hylton

Lucas

Petreaca

2020

Genes

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The fission yeast—Schizosaccharomyces pombe—has emerged as a powerful tractable system for studying DNA damage repair. Over the last few decades, several powerful in vivo genetic assays have been developed to study outcomes of mitotic recombination, the major repair mechanism of DNA double strand breaks and stalled or collapsed DNA replication forks. These assays have significantly increased our understanding of the molecular mechanisms underlying the DNA damage response pathways. Here, we review the assays that have been developed in fission yeast to study mitotic recombination.

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“…Nonetheless, mice expressing mutant RNASEH2A and RNASEH2B alleles show that these mutations result in the direct accumulation of nucleic acids that induce IFN through cGAS/STING signaling (Mackenzie et al, 2016; Pokatayev et al, 2016). Evidence suggests that the specific origin of nucleic acids that leads to RNase H2-mediated inflammatory disease may occur through DNA damage responses as well as recognition of retroelements (Bartsch et al, 2017, 2018; Günther et al, 2015; Zhao et al, 2018). Furthermore, two recent studies have also shown that DNA damage leading to the formation of micronuclei induces an IFN response through cGAS and that this occurs in frequently in the absence of RNASEH2B (Harding et al, 2017; Mackenzie et al, 2017).…”

Section: Intracellular Recognition Of Dnamentioning

confidence: 99%

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

Matz

Guzman

Goodman

2019

Nucleic Acid Sensing and Immunity - Part B

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Innate immunity, the first line of defense against invading pathogens, is an ancient form of host defense found in all animals, from sponges to humans. During infection, innate immune receptors recognize conserved molecular patterns, such as microbial surface molecules, metabolites produces during infection, or nucleic acids of the microbe’s genome. When initiated, the innate immune response activates a host defense program that leads to the synthesis proteins capable of pathogen killing. In mammals, the induction of cytokines during the innate immune response leads to the recruitment of professional immune cells to the site of infection, leading to an adaptive immune response. While a fully functional innate immune response is crucial for a proper host response and curbing microbial infection, if the innate immune response is dysfunctional and is activated in the absence of infection, autoinflammation and autoimmune disorders can develop. Therefore, it follows that the innate immune response must be tightly controlled to avoid an autoimmune response from host-derived molecules, yet still unencumbered to respond to infection. In this review, we will focus on the innate immune response activated from cytosolic nucleic acids, derived from the microbe or host itself. We will depict how viruses and bacteria activate these nucleic acid sensing pathways and their mechanisms to inhibit the pathways. We will also describe the autoinflammatory and autoimmune disorders that develop when these pathways are hyperactive. Finally, we will discuss gaps in knowledge with regard to innate immune response failure and identify where further research is needed.

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RNase H eliminates R‐loops that disrupt DNA replication but is nonessential for efficient DSB repair

Cited by 68 publications

References 68 publications

DNA:RNA hybrids form at DNA double-strand breaks in transcriptionally active loci

DNA:RNA hybrids form at DNA double-strand breaks in transcriptionally active loci

Schizosaccharomyces pombe Assays to Study Mitotic Recombination Outcomes

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

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