PARP1 associates with R-loops to promote their resolution and genome stability

Natalie Laspata; Parminder Kaur; Sofiane Yacine Mersaoui; Daniela Muoio; Zhiyan Silvia Liu; Maxwell Henry Bannister; Hai Dang Nguyen; Caroline Curry; John M. Pascal; Guy G. Poirier; Hong Wang; Jean Yves Masson; Elise Fouquerel

doi:10.1093/nar/gkad066

PARP1 associates with R-loops to promote their resolution and genome stability

Natalie Laspata, Parminder Kaur, Sofiane Yacine Mersaoui, Daniela Muoio, Zhiyan Silvia Liu, Maxwell Henry Bannister, Hai Dang Nguyen, Caroline Curry, John M. Pascal, Guy G. Poirier, Hong Wang, Jean Yves Masson, Elise Fouquerel

Pharmacology

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

Abstract

PARP1 is a DNA-dependent ADP-Ribose transferase with ADP-ribosylation activity that is triggered by DNA breaks and non-B DNA structures to mediate their resolution. PARP1 was also recently identified as a component of the R-loop-associated protein-protein interaction network, suggesting a potential role for PARP1 in resolving this structure. R-loops are three-stranded nucleic acid structures that consist of a RNA-DNA hybrid and a displaced non-template DNA strand. R-loops are involved in crucial physiological processes but can also be a source of genome instability if persistently unresolved. In this study, we demonstrate that PARP1 binds R-loops in vitro and associates with R-loop formation sites in cells which activates its ADP-ribosylation activity. Conversely, PARP1 inhibition or genetic depletion causes an accumulation of unresolved R-loops which promotes genomic instability. Our study reveals that PARP1 is a novel sensor for R-loops and highlights that PARP1 is a suppressor of R-loop-associated genomic instability.

Original language	English (US)
Pages (from-to)	2215-2237
Number of pages	23
Journal	Nucleic acids research
Volume	51
Issue number	5
DOIs	https://doi.org/10.1093/nar/gkad066
State	Published - Mar 21 2023

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© 2023 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.

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abstract = "PARP1 is a DNA-dependent ADP-Ribose transferase with ADP-ribosylation activity that is triggered by DNA breaks and non-B DNA structures to mediate their resolution. PARP1 was also recently identified as a component of the R-loop-associated protein-protein interaction network, suggesting a potential role for PARP1 in resolving this structure. R-loops are three-stranded nucleic acid structures that consist of a RNA-DNA hybrid and a displaced non-template DNA strand. R-loops are involved in crucial physiological processes but can also be a source of genome instability if persistently unresolved. In this study, we demonstrate that PARP1 binds R-loops in vitro and associates with R-loop formation sites in cells which activates its ADP-ribosylation activity. Conversely, PARP1 inhibition or genetic depletion causes an accumulation of unresolved R-loops which promotes genomic instability. Our study reveals that PARP1 is a novel sensor for R-loops and highlights that PARP1 is a suppressor of R-loop-associated genomic instability.",

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AU - Liu, Zhiyan Silvia

AU - Bannister, Maxwell Henry

AU - Nguyen, Hai Dang

AU - Curry, Caroline

AU - Pascal, John M.

AU - Poirier, Guy G.

AU - Wang, Hong

AU - Masson, Jean Yves

AU - Fouquerel, Elise

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PARP1 associates with R-loops to promote their resolution and genome stability

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