R-loops as Janus-faced modulators of DNA repair

Marnef, Aline; Legube, Gaëlle

doi:10.1038/s41556-021-00663-4

Cited by 116 publications

(98 citation statements)

References 150 publications

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“…For example, while RBM14 and METTL3 stabilize RNA:DNA hybrids to promote DSB repair, DDX5, DDX1, SETX, and many other RBPs instead mediate their resolution (Li et al, 2008(Li et al, , 2016Cohen et al, 2018;Jang et al, 2020;Yu et al, 2020;Zhang et al, 2020;Sessa et al, 2021). This dichotomy of RBP functions with regards to RNA:DNA hybrids further supports the idea that the context and timing of these structures is critical for efficient DSB repair (Marnef and Legube, 2021). Determining how RNA:DNA hybrids promote certain DSB repair steps while inhibiting others, and how this is regulated by RBPs, are important open questions.…”

Section: Final Remarksmentioning

confidence: 72%

“…Why DDX5 needs to be removed from damaged chromatin as soon as it clears RNA-associated DNA repair impediments is not clear, but it might be related to the observation that not all RNA:DNA hybrids are detrimental to the repair process. Instead, the context of their formation seems to determine whether they need to be removed or stabilized (Marnef and Legube, 2021). A consequence of this RNA:DNA hybrid plasticity is that the activity of the RBPs that control the processing of these structures needs to be tightly regulated, and the exclusion of these proteins at certain repair steps might be a reflection of this regulation.…”

Section: Final Remarksmentioning

confidence: 99%

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New Faces of old Friends: Emerging new Roles of RNA-Binding Proteins in the DNA Double-Strand Break Response

Klaric

Wüst

Panier

2021

Front. Mol. Biosci.

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DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions. To protect genomic stability and ensure cell homeostasis, cells mount a complex signaling-based response that not only coordinates the repair of the broken DNA strand but also activates cell cycle checkpoints and, if necessary, induces cell death. The last decade has seen a flurry of studies that have identified RNA-binding proteins (RBPs) as novel regulators of the DSB response. While many of these RBPs have well-characterized roles in gene expression, it is becoming increasingly clear that they also have non-canonical functions in the DSB response that go well beyond transcription, splicing and mRNA processing. Here, we review the current understanding of how RBPs are integrated into the cellular response to DSBs and describe how these proteins directly participate in signal transduction, amplification and repair at damaged chromatin. In addition, we discuss the implications of an RBP-mediated DSB response for genome instability and age-associated diseases such as cancer and neurodegeneration.

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Section: Final Remarksmentioning

confidence: 72%

Section: Final Remarksmentioning

confidence: 99%

New Faces of old Friends: Emerging new Roles of RNA-Binding Proteins in the DNA Double-Strand Break Response

Klaric

Wüst

Panier

2021

Front. Mol. Biosci.

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“…In agreement with our observations, analysis of DSBs-induced genome-wide in human cell cultures has recently shown that pre-existing transcription is critical for the formation of DNA-RNA hybrids at breaks ( Bader and Bushell, 2020 ; Cohen et al, 2018 ). Based on the observation that R-loops are induced in mutants with increased RNA polymerase II backtracking in human cells ( Zatreanu et al, 2019 ), it has been proposed that RNA polymerase backtracking could be the source of hybrids upstream of the break site ( Marnef and Legube, 2021 ). However, we cannot discern from the DRIP analysis whether hybrids at both sides of the break are formed by different or the same RNA molecule.…”

Section: Discussionmentioning

confidence: 99%

“…In accordance, cells have evolved multiple mechanisms to counteract their formation including RNA coating by RNA biogenesis factors, such as the THO complex, DNA-RNA unwinding by different helicases including Senataxin and UAP56/DDX39B, RNA degradation by RNase H enzymes, as well as DNA repair-mediated removal ( García-Muse and Aguilera, 2019 ). Despite evidence indicating that DSBs promote DNA-RNA hybridization, the effect of such hybrids at DSBs is yet unclear ( Aguilera and Gómez-González, 2017 ; Marnef and Legube, 2021 ). Thus, whereas different helicases have been shown to remove DNA-RNA hybrids at DSBs ( Cohen et al, 2018 ; Li et al, 2016 ; Sessa et al, 2021 ; Yu et al, 2020 ), other reports postulated that RNA molecules could act as a functional intermediate for DSB repair ( D'Alessandro et al, 2018 ; Keskin et al, 2014 ; Liu et al, 2021 ; Lu et al, 2018 ; Ohle et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

DNA-RNA hybrids at DSBs interfere with repair by homologous recombination

Ortega

Mérida-Cerro

Rondón

et al. 2021

eLife

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DNA double strand breaks (DSBs) are the most harmful DNA lesions and their repair is crucial for cell viability and genome integrity. The readout of DSB repair may depend on whether DSBs occur at transcribed versus non-transcribed regions. Some studies have postulated that DNA-RNA hybrids form at DSBs to promote recombinational repair, but others have challenged this notion. To directly assess whether hybrids formed at DSBs promote or interfere with recombinational repair we have used plasmid and chromosomal-based systems for the analysis of DSB-induced recombination in Saccharomyces cerevisiae. We show that, as expected, DNA-RNA hybrid formation is stimulated at DSBs. In addition, mutations that promote DNA-RNA hybrid accumulation, such as hpr1∆ and rnh1∆ rnh201∆, cause high levels of plasmid loss when DNA breaks are induced at sites that are transcribed. Importantly, we show that high levels or unresolved DNA-RNA hybrids at the breaks interfere with their repair by homologous recombination. This interference is observed for both plasmid and chromosomal recombination and is independent of whether the DSB is generated by endonucleolytic cleavage or by DNA replication. These data support a model in which DNA-RNA hybrids form fortuitously at DNA breaks during transcription, and need to be removed to allow recombinational repair, rather than playing a positive role.

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“…R-loops are 3–stranded nucleic acid structures that are linked to transcription and can contribute to replication stress 10 . R-loops are comprised of an RNA/DNA hybrid and a displaced single-stranded DNA (ssDNA), for recent reviews see 11 – 13 . R-loops form within the genome at actively transcribed genes preferentially occurring at gene promoters and terminators.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-induced SETX links replication stress with the unfolded protein response

et al. 2021

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Tumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. Therefore, suggesting that, SETX plays a role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.

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R-loops as Janus-faced modulators of DNA repair

Cited by 116 publications

References 150 publications

New Faces of old Friends: Emerging new Roles of RNA-Binding Proteins in the DNA Double-Strand Break Response

New Faces of old Friends: Emerging new Roles of RNA-Binding Proteins in the DNA Double-Strand Break Response

DNA-RNA hybrids at DSBs interfere with repair by homologous recombination

Hypoxia-induced SETX links replication stress with the unfolded protein response

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