Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis

Hashimoto, Yoshitami; Chaudhuri, Arnab Ray; Lopes, Massimo; Costanzo, Vincenzo

doi:10.1038/nsmb.1927

Cited by 494 publications

(615 citation statements)

References 46 publications

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“…[3][4][5] This notion is strengthened by our observation that WRNIP1 functions in the same pathway as BRCA2, as proved by their physical interaction and lack of additive effect on DNA nascent strand degradation when we downregulated both in cells. The inability to form a RAD51-coated nucleofilament renders BRCA2-deficient cells susceptible to MRE11 nucleolytic degradation.…”

supporting

confidence: 57%

“…In this regard, breast cancer type 2 susceptibility protein (BRCA2) and radiation sensitive 51 protein (RAD51) protect nascent DNA strands from the pathologic degradation mediated by the exonucleolytic activity of meiotic recombination enzyme 11 (MRE11), implicating a distinct role from the repair of lesions formed at stalled replication forks. [3][4][5] Despite extensive research, how these HR components accomplish the resolution of fork stalling, and whether other proteins collaborate with them in this task, has not yet been fully elucidated.…”

mentioning

confidence: 99%

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WRNIP1: A new guardian of genome integrity at stalled replication forks

Leuzzi

Marabitti

Pichierri

et al. 2016

Molecular & Cellular Oncology

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supporting

confidence: 57%

mentioning

confidence: 99%

WRNIP1: A new guardian of genome integrity at stalled replication forks

Leuzzi

Marabitti

Pichierri

et al. 2016

Molecular & Cellular Oncology

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“…Regardless of their source, postreplicative ssDNA gaps can certainly contribute to explain the observed accumulation of RAD51 in PARG-depleted cells. Intriguingly, RAD51 was previously reported to limit ssDNA accumulation at yeast and Xenopus replication forks, especially in response to genotoxic stress (40). Furthermore, RAD51 itself and several HR and Fanconi anemia factors were shown to prevent excessive degradation of newly synthesized DNA in response to replication stress (41,42).…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-Ribosyl) Glycohydrolase Prevents the Accumulation of Unusual Replication Structures during Unperturbed S Phase

Chaudhuri

Ahuja

Herrador

et al. 2015

Molecular and Cellular Biology

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Poly(ADP-ribosyl)ation (PAR) has been implicated in various aspects of the cellular response to DNA damage and genome stability. Although 17 human poly(ADP-ribose) polymerase (PARP) genes have been identified, a single poly(ADP-ribosyl) glycohydrolase (PARG) mediates PAR degradation. Here we investigated the role of PARG in the replication of human chromosomes. We show that PARG depletion affects cell proliferation and DNA synthesis, leading to replication-coupled H2AX phosphorylation. Furthermore, PARG depletion or inhibition per se slows down individual replication forks similarly to mild chemotherapeutic treatment. Electron microscopic analysis of replication intermediates reveals marked accumulation of reversed forks and single-stranded DNA (ssDNA) gaps in unperturbed PARG-defective cells. Intriguingly, while we found no physical evidence for chromosomal breakage, PARG-defective cells displayed both ataxia-telangiectasia-mutated (ATM) and ataxia-Rad3-related (ATR) activation, as well as chromatin recruitment of standard double-strand-break-repair factors, such as 53BP1 and RAD51. Overall, these data prove PAR degradation to be essential to promote resumption of replication at endogenous and exogenous lesions, preventing idle recruitment of repair factors to remodeled replication forks. Furthermore, they suggest that fork remodeling and restarting are surprisingly frequent in unperturbed cells and provide a molecular rationale to explore PARG inhibition in cancer chemotherapy.C ellular responses are crucial for the adaptability and survival of a cell exposed to different types of endogenous and exogenous stress. The DNA damage response (DDR) consists of one such defense mechanism in response to different types of insults to the DNA. Poly(ADP)ribosylation of proteins is one of the quickest cellular responses to DNA damage and is brought about by proteins of the poly(ADP) ribose polymerase family (PARP), mostly PARP1 (1). Upon being recruited to sites of the DNA damage, NAD ϩ is used as a substrate by PARP to synthesize negatively charged poly(ADP-ribosyl)ation (PAR) polymers onto itself and also its target proteins (1). Through this posttranslational modification, PARP targets a variety of nuclear proteins to facilitate the recruitment of DNA repair factors to sites of damage (2, 3). Accordingly, PARP-1 or PARP-2-deficient mice and mouse embryonic fibroblasts show chromosomal aberrations and various DNA repair defects (4-6).Inhibition of PARP has become a promising therapeutic approach for the treatment of certain types of cancer (7). It was shown that PARP inhibitors could selectively kill homologous recombination (HR)-deficient cancer cells (8, 9). The reason behind the sensitivity of HR-deficient cells to PARP inhibition is thought to be the accumulation of single-stranded DNA (ssDNA) breaks in the absence of PAR synthesis, leading to replication fork collapse and double-stranded breaks (DSBs), which would then require HR factors for repair (8,10). Recently, PARP activity has also been reported to play a ro...

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“…Experiments in Xenopus cell extracts showed that formation of RAD51 filaments at stalled replication protects from degradation by the Mre11 nuclease (Hashimoto et al 2010). Similar observations were made in BRCA2-deficient mammalian cells, in which fork protection was found to be independent of RAD54, suggesting that it is the RAD51 -ssDNA filament structure and not its ability for DNA strand invasion that protects from Mre11 degradation (Schlacher et al 2011).…”

Section: Reversibility At the Rad51 Nucleoprotein Filament Stage: Resmentioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

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Recombination is a central process to stably maintain and transmit a genome through somatic cell divisions and to new generations. Hence, recombination needs to be coordinated with other events occurring on the DNA template, such as DNA replication, transcription, and the specialized chromosomal functions at centromeres and telomeres. Moreover, regulation with respect to the cell-cycle stage is required as much as spatiotemporal coordination within the nuclear volume. These regulatory mechanisms impinge on the DNA substrate through modifications of the chromatin and directly on recombination proteins through a myriad of posttranslational modifications (PTMs) and additional mechanisms. Although recombination is primarily appreciated to maintain genomic stability, the process also contributes to gross chromosomal arrangements and copy-number changes. Hence, the recombination process itself requires quality control to ensure high fidelity and avoid genomic instability. Evidently, recombination and its regulatory processes have significant impact on human disease, specifically cancer and, possibly, neurodegenerative diseases.

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Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis

Cited by 494 publications

References 46 publications

WRNIP1: A new guardian of genome integrity at stalled replication forks

WRNIP1: A new guardian of genome integrity at stalled replication forks

Poly(ADP-Ribosyl) Glycohydrolase Prevents the Accumulation of Unusual Replication Structures during Unperturbed S Phase

Regulation of Recombination and Genomic Maintenance

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