BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment

D’Alessandro, Giuseppina; Whelan, Donna R.; Howard, Sean; Vitelli, Valerio; Renaudin, Xavier; Adamowicz, Marek; Iannelli, Fabio; Jones-Weinert, Corey Winston; Lee, Mi-Young; Matti, Valentina; Lee, Wei Ting C.; Morten, Michael J.; Venkitaraman, Ashok R.; Ćejka, Petr; Rothenberg, Eli; Fagagna, Fabrizio d’Adda di

doi:10.1038/s41467-018-07799-2

Cited by 196 publications

(234 citation statements)

References 72 publications

(101 reference statements)

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“…This is consistent with the idea that it is the RNA produced in cis who invades the duplex DNA, a reaction that can be facilitated by increasing the negative supercoiling of DNA as well as by nicking the DNA template (Roy, Zhang, Lu, Hsieh, & Lieber, 2010). The evidence of DNA:RNA hybrid formation at breaks has matured in the last years (Cohen et al, 2018;D'Alessandro et al, 2018;L. Li et al, 2016;Ohle et al, 2016;Teng et al, 2018;Yasuhara et al, 2018) although the source and role of such hybrids remains still controversial Puget, Miller, & Legube, 2019).…”

Section: Introductionsupporting

confidence: 77%

“…Whereas some claim that DNA:RNA hybrids detected around DNA breaks mostly accumulate at transcribing sites (Cohen et al, 2018), in agreement with their co-transcriptional formation, others suggest that there is no preference for DNA:RNA hybrids to form at transcribed loci (D'Alessandro et al, 2018), implying an scenario in which DNA:RNA hybrids at breaks sites would form either de novo or with RNAs produced in trans.…”

Section: Introductionmentioning

confidence: 97%

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Harmful DNA:RNA hybrids are formedin cisand in a Rad51-independent manner

Aguilera

Gómez-González

Lafuente-Barquero

et al. 2020

Preprint

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DNA:RNA hybrids constitute a well-known source of recombinogenic DNA damage. The current literature is in agreement with DNA:RNA hybrids being produced co-transcriptionally by the invasion of the nascent RNA molecule produced in cis with its DNA template. However, it has also been suggested that recombinogenic DNA:RNA hybrids could be facilitated by the invasion of RNA molecules produced in trans in a Rad51-mediated reaction. Here, we tested the possibility that such DNA:RNA hybrids produced in trans constitute a source of recombinogenic DNA damage taking advantage of Rad51independent single-strand annealing recombination assays and new constructs designed to induce expression of mRNA transcripts in trans in the yeast Saccharomyces cerevisiae. We show that unscheduled and recombinogenic DNA:RNA hybrids are formed in cis during transcription and in a Rad51independent manner.

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Section: Introductionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 97%

Harmful DNA:RNA hybrids are formedin cisand in a Rad51-independent manner

Aguilera

Gómez-González

Lafuente-Barquero

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…A variety of experimental strategies have been applied in recent years to study the occurrence of DNA:RNA hybrids at sites of DNA damage. [ 28,29,52,56,57 ] These studies support the conclusion that DNA lesions in active transcription units cause RNAPII arrest and promote R‐loop formation, and DNA:RNA hybrids have been proposed to play a key role in promoting accurate DSB repair by contributing to the recruitment of DNA repair factors such as RAD52. [ 58 ] Interestingly, not only promoter‐dependent transcripts but also dilncRNAs can engage in DNA:RNA hybrid formation.…”

Section: Dilncrnas Produced At Dsbs Engage In Dna:rna Hybrid Formationmentioning

confidence: 61%

RNA at DNA Double‐Strand Breaks: The Challenge of Dealing with DNA:RNA Hybrids

2020

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RNA polymerase II is recruited to DNA double-strand breaks (DSBs), transcribes the sequences that flank the break and produces a novel RNA type that has been termed damage-induced long non-coding RNA (dilncRNA). DilncRNAs can be processed into short, miRNA-like molecules or degraded by different ribonucleases. They can also form double-stranded RNAs or DNA:RNA hybrids. The DNA:RNA hybrids formed at DSBs contribute to the recruitment of repair factors during the early steps of homologous recombination (HR) and, in this way, contribute to the accuracy of the DNA repair. However, if not resolved, the DNA:RNA hybrids are highly mutagenic and prevent the recruitment of later HR factors. Here recent discoveries about the synthesis, processing, and degradation of dilncRNAs are revised. The focus is on RNA clearance, a necessary step for the successful repair of DSBs and the aim is to reconcile contradictory findings on the effects of dilncRNAs and DNA:RNA hybrids in HR.

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“…Our data indicate that Npl3 presence at short telomeres contributes to R‐loop stability and thereby promotes telomere recombination to prevent premature senescence. These results add to our mechanistic understanding of how R‐loop regulation promotes the repair of short telomeres by HDR during senescence and may also be relevant for the repair of double‐strand breaks (DSBs), where R‐loops have recently been demonstrated to promote recombination‐based repair .…”

Section: Introductionmentioning

confidence: 80%

Npl3 stabilizes R‐loops at telomeres to prevent accelerated replicative senescence

et al. 2020

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Telomere shortening rates must be regulated to prevent premature replicative senescence. TERRA R‐loops become stabilized at critically short telomeres to promote their elongation through homology‐directed repair (HDR), thereby counteracting senescence onset. Using a non‐bias proteomic approach to detect telomere binding factors, we identified Npl3, an RNA‐binding protein previously implicated in multiple RNA biogenesis processes. Using chromatin immunoprecipitation and RNA immunoprecipitation, we demonstrate that Npl3 interacts with TERRA and telomeres. Furthermore, we show that Npl3 associates with telomeres in an R‐loop‐dependent manner, as changes in R‐loop levels, for example, at short telomeres, modulate the recruitment of Npl3 to chromosome ends. Through a series of genetic and biochemical approaches, we reveal that Npl3 binds to TERRA and stabilizes R‐loops at short telomeres, which in turn promotes HDR and prevents premature replicative senescence onset. This may have implications for diseases associated with excessive telomere shortening.

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BRCA2 controls DNA:RNA hybrid level at DSBs by mediating RNase H2 recruitment

Cited by 196 publications

References 72 publications

Harmful DNA:RNA hybrids are formedin cisand in a Rad51-independent manner

Harmful DNA:RNA hybrids are formedin cisand in a Rad51-independent manner

RNA at DNA Double‐Strand Breaks: The Challenge of Dealing with DNA:RNA Hybrids

Npl3 stabilizes R‐loops at telomeres to prevent accelerated replicative senescence

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