Fork Cleavage-Religation Cycle and Active Transcription Mediate Replication Restart after Fork Stalling at Co-transcriptional R-Loops

Chappidi, Nagaraja; Naščáková, Zuzana; Boleslavska, Barbora; Zellweger, Ralph; Isik, Esin; Andrš, Martin; Menon, Shruti; Dobrovolná, Jana; Pogliano, Chiara Balbo; Matos, Joao; Porro, Antônio; Lopes, Massimo; Janscak, Pavel

doi:10.1016/j.molcel.2019.10.026

Cited by 119 publications

(154 citation statements)

References 46 publications

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“…Previous findings reported that the structure-specific nucleases Xeroderma Pigmentosum Complementation Group F (XPF) and XPG directly cleave R-loops to promote their resolution [55]. Mounting evidences suggest that R-loop-induced ATR activation is independent of XPG but requires the Mutagen Sensitive 81 (MUS81) endonuclease [43,49,56]. By contrast, in the absence of WRN, XPG-mediated transient DSBs deriving from R-loop processing are responsible for ATM pathway activation [18].…”

Section: Discussionmentioning

confidence: 99%

Checkpoint Defects Elicit a WRNIP1-Mediated Response to Counteract R-Loop-Associated Genomic Instability

Marabitti

Lillo

Malacaria

et al. 2020

Cancers

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Conflicts between replication and transcription are a common source of genomic instability, a characteristic of almost all human cancers. Aberrant R-loops can cause a block to replication fork progression. A growing number of factors are involved in the resolution of these harmful structures and many perhaps are still unknown. Here, we reveal that the Werner interacting protein 1 (WRNIP1)-mediated response is implicated in counteracting aberrant R-loop accumulation. Using human cellular models with compromised Ataxia-Telangiectasia and Rad3-Related (ATR)-dependent checkpoint activation, we show that WRNIP1 is stabilized in chromatin and is needed for maintaining genome integrity by mediating the Ataxia Telangiectasia Mutated (ATM)-dependent phosphorylation of Checkpoint kinase 1 (CHK1). Furthermore, we demonstrated that loss of Werner Syndrome protein (WRN) or ATR signaling leads to formation of R-loop-dependent parental ssDNA upon mild replication stress, which is covered by Radiorestistance protein 51 (RAD51). We prove that Werner helicase-interacting protein 1 (WRNIP1) chromatin retention is also required to stabilize the association of RAD51 with ssDNA in proximity of R-loops. Therefore, in these pathological contexts, ATM inhibition or WRNIP1 abrogation is accompanied by increased levels of genomic instability. Overall, our findings suggest a novel function for WRNIP1 in preventing R-loop-driven genome instability, providing new clues to understand the way replication–transcription conflicts are handled.

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Section: Discussionmentioning

confidence: 99%

Checkpoint Defects Elicit a WRNIP1-Mediated Response to Counteract R-Loop-Associated Genomic Instability

Marabitti

Lillo

Malacaria

et al. 2020

Cancers

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“…Previous findings reported that the structure-specific nucleases XPF and XPG directly cleave Rloops to promote their resolution (Sollier et al, 2014). Mounting evidences suggest that R-loopinduced ATR activation is independent of XPG, but requires the MUS81 endonuclease (Pichierri et al, 2001;Matos et al, 2019;Chappidi et al, 2019). By contrast, in the absence of WRN, XPGmediated transient DSBs deriving from R-loop processing are responsible for ATM pathway activation .…”

Section: Discussionmentioning

confidence: 99%

Checkpoint defects require WRNIP1 to counteract R-loop-associated genomic instability

Franchitto

Marabitti

Lillo

et al. 2019

Preprint

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Conflicts between replication and transcription are common source of genome instability and many factors participate in prevention or removal of harmful R-loops. Here, we demonstrate that a WRNIP1-mediated response plays an important role in counteracting accumulation of aberrant Rloops. Using human cellular models with compromised ATR-dependent checkpoint activation, we show that WRNIP1 is stabilised in chromatin and is needed for maintaining genome integrity by mediating the ATM-dependent phosphorylation of CHK1. Furthermore, we show that loss of WRN or ATR signalling leads to accumulation of R-loop-dependent parental ssDNA, which is covered by RAD51. We demonstrate that WRNIP1 chromatin retention is also required to stabilise the association of RAD51 with ssDNA in proximity of R-loops. Therefore, in these pathological contexts, ATM inhibition or WRNIP1 abrogation is accompanied by increased levels of genomic instability. Overall our findings reveal a novel function of WRNIP1 in preventing R-loop-driven genome instability, providing new clues to understand the way replication-transcription conflicts are resolved.3

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“…By another mechanism, RECQL5 is proposed to collaborate with MUS81 endonuclease to process stalled replication forks at common fragile sites [285]. In addition, RECQL5 was reported to disrupt RAD51 filaments on stalled forks at common fragile sites, making the transition from fork stalling at R-loops to replication restart go smoothly [286].…”

Section: Replication Stressmentioning

confidence: 99%

“…Based on further studies in human cells, a model was proposed that RECQL5 helicase helps to prevent replication-transcription collisions [284]. A role for RECQL5 in restarting DNA replication after encounters with co-transcriptional R-loops and in collaboration with numerous other DNA repair factors was proposed recently [286].…”

Section: Transcriptional Regulationmentioning

confidence: 99%

History of DNA Helicases

Brosh

Matson

2020

Genes

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Since the discovery of the DNA double helix, there has been a fascination in understanding the molecular mechanisms and cellular processes that account for: (i) the transmission of genetic information from one generation to the next and (ii) the remarkable stability of the genome. Nucleic acid biologists have endeavored to unravel the mysteries of DNA not only to understand the processes of DNA replication, repair, recombination, and transcription but to also characterize the underlying basis of genetic diseases characterized by chromosomal instability. Perhaps unexpectedly at first, DNA helicases have arisen as a key class of enzymes to study in this latter capacity. From the first discovery of ATP-dependent DNA unwinding enzymes in the mid 1970’s to the burgeoning of helicase-dependent pathways found to be prevalent in all kingdoms of life, the story of scientific discovery in helicase research is rich and informative. Over four decades after their discovery, we take this opportunity to provide a history of DNA helicases. No doubt, many chapters are left to be written. Nonetheless, at this juncture we are privileged to share our perspective on the DNA helicase field – where it has been, its current state, and where it is headed.

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Fork Cleavage-Religation Cycle and Active Transcription Mediate Replication Restart after Fork Stalling at Co-transcriptional R-Loops

Cited by 119 publications

References 46 publications

Checkpoint Defects Elicit a WRNIP1-Mediated Response to Counteract R-Loop-Associated Genomic Instability

Checkpoint Defects Elicit a WRNIP1-Mediated Response to Counteract R-Loop-Associated Genomic Instability

Checkpoint defects require WRNIP1 to counteract R-loop-associated genomic instability

History of DNA Helicases

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