PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination

Bryant, Helen E.; Petermann, Eva; Schultz, Niklas; Jemth, Ann-Sofie; Loseva, Olga; Issaeva, Natalia; Johansson, Fredrik; Fernandez, Serena; McGlynn, Peter; Helleday, Thomas

doi:10.1038/emboj.2009.206

Cited by 539 publications

(559 citation statements)

References 65 publications

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“…Of note, the binding of p-RPA to the replication fork was also induced after HU, but it was less in PARP1 À / À cells (Fig. 2e), possibly because of PARP1's role in MRN-mediated resection at the replication fork that activates ATR 48 . Despite a great effort, all available PAR and PARP1 antibodies failed to visualize PAR and PARP1 binding at the replication fork, probably because of stringent technical requirement of this assay.…”

Section: Resultsmentioning

confidence: 98%

“…S2). As PARP1 is required for the recruitment of the MRN complex to resect DNA at the stalled replication forks 58,59 , the impaired activation of Chk1 in PAR-deficient conditions might be due to the decreased resection at stalled forks, leading to less RPA-ATR-Chk1 activation. However, since ATR is dispensable for Chk1-PAR binding and Chk1 is enriched at the replication fork without HU treatment, less p-RPA after damage is unlikely to contribute significantly to the accelerated dissociation of Chk1 from the replication fork.…”

Section: Discussionmentioning

confidence: 99%

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Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation

et al. 2013

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Damaged replication forks activate poly(ADP-ribose) polymerase 1 (PARP1), which catalyses poly(ADP-ribose) (PAR) formation; however, how PARP1 or poly(ADP-ribosyl)ation is involved in the S-phase checkpoint is unknown. Here we show that PAR, supplied by PARP1, interacts with Chk1 via a novel PAR-binding regulatory (PbR) motif in Chk1, independent of ATR and its activity. iPOND studies reveal that Chk1 associates readily with the unperturbed replication fork and that PAR is required for efficient retention of Chk1 and phosphorylated Chk1 at the fork. A PbR mutation, which disrupts PAR binding, but not the interaction with its partners Claspin or BRCA1, impairs Chk1 and the S-phase checkpoint activation, and mirrors Chk1 knockdown-induced hypersensitivity to fork poisoning. We find that long chains, but not short chains, of PAR stimulate Chk1 kinase activity. Collectively, we disclose a previously unrecognized mechanism of the S-phase checkpoint by PAR metabolism that modulates Chk1 activity at the replication fork.

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation

et al. 2013

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“…PARP-1 has been described to participate in double strand break repair [37]. Nicolás and co-workers have identified the accumulation of double strand breaks in PARP-2 -/-murine thymocytes [38].…”

Section: Parp-2 In the Maintenance Of Genomic Integritymentioning

confidence: 99%

“…This observation is in line with previous report by Yelamos and colleagues [24] who suggested that PARP-2 interacts with the Ku proteins, mediators of double strand break repair. Moreover, Robert and colleagues have identified PARP-2 as a suppressor of recombination during immunoglobulin class switch events in murine and human B cells [39], while Bryant et al have suggested that both PARP-1 and -2 are essential in resolving blocked replication forks by homologous recombination in CHO and murine embryonic fibroblasts (MEFs) [37,40]. The fact that the ATM/PARP-2 double knockout genotype is embryonic lethal [20] further supports the involvement of PARP-2 in double strand break repair during replication.…”

Section: Parp-2 In the Maintenance Of Genomic Integritymentioning

confidence: 99%

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Szántó

Brunyánszki

Kiss

et al. 2012

Cell. Mol. Life Sci.

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Abstract:Poly(ADP-ribose) polymerase (PARP)-2 is a nuclear enzyme that belongs to the PARP family and PARP-2 is responsible for 5-15% of total cellular PARP activity. PARP-2 was originally described in connection to DNA repair and in physiological and pathophysiological processes associated with genome maintenance (e.g. centromere and telomere protection, spermiogenesis, thymopoesis, azoospermia and tumorigenesis). Recent reports identified important rearrangements in gene expression upon the knockout of PARP-2. Such rearrangements heavily impact on inflammation and metabolism. Metabolic effects are mediated through modifying PPARg and SIRT1 function. Altered gene expression gives rise to a complex phenotype characterized primarily by enhanced mitochondrial activity that results both in beneficial (loss of fat, enhanced insulin sensitivity) and in disadvantageous (pancreatic beta cell hypofunction upon high fat feeding) consequences. Enhanced mitochondrial biogenesis provides protection in oxidative stress related diseases. Hereby, we review the recent developments in PARP-2 research with special attention to the involvement of PARP-2 in transcriptional and metabolic regulation. We would like to thank the referee for his/her efforts to further improve our manuscript.1. Page 2 -the modifications here are fairly minimalistic and the abbreviations ARTD2 and ARTD1 are not even defined. Powered by Editorial Manager® and Preprint Manager® from Aries Systems Corporationand ARTD1 are not even defined.In the corresponding section we incorporated the basic information on the newly proposed nomenclature in our previous version upon the suggestion of the Reviewer. We agree with the Reviewer that the appearance of the new nomenclature in our manuscript is important. Moreover, in the current version we added ARTD-2 as a keyword to help those future readers that follow the new nomenclature. The fact that ARTD1 is the equivalent of PARP-1 is defined in the chapter "PARP superfamily" second paragraph, first row. We added the abbreviation of ARDT-2 in the last sentence in the first paragraph of the chapter "The PARP superfamily". We think that these are sufficient for the understanding of the position of PARP-2 in the PARP/ARTD superfamily.We would like to note here, that the proposed new nomenclature did not gain ground in the scientific community yet. There are only 3 relevant papers on Medline for the keyword ARTD1, ARTD2 or ARTD (since 2010, the publication of the paper by In summary, we are confident that our review sufficiently takes the new nomenclature into consideration despite of the fact that it is not yet accepted by the scientific community. Sequence homology modeling was carried out by Ame and co-workers (Ame et al. Bioessays. 26:882-893. 2004). They classified sequences as PARPs on the basis of sequence homology, therefore sequence homology does exist. However, mutation(s) in a sequence does not necessarily mean that sequence homology is lost. In the incriminated text, mutations mean rather point mutations that aff...

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“…The main role proposed for PARylation in genome stability is linked to the recruitment of specific proteins through PAR binding domains such as the macro domain. At replication forks, the establishment of a PAR scaffold is necessary for the reversal of forks generated by TopI inhibition [73,74]. In addition, PAR protects reversed forks from MRE11 mediated degradation by either physically impeding the access to the fork or by cooperating in the recruitment of BRCA2 and RAD51.…”

Section: Rs As a Fuel Of Tumorogenesismentioning

confidence: 99%

Replication stress and cancer: It takes two to tango

Lecona

Fernández-Capetillo

2014

Experimental Cell Research

119

107

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Problems arising during DNA replication require the activation of the ATR-CHK1 pathway to ensure the stabilization and repair of the forks, and to prevent the entry into mitosis with unreplicated genomes. Whereas the pathway is essential at the cellular level, limiting its activity is particularly detrimental for some cancer cells. Here we review the links between replication stress (RS) and cancer, which provide a rationale for the use of ATR and Chk1 inhibitors in chemotherapy. First, we describe how the activation of oncogene-induced RS promotes genome rearrangements and chromosome instability, both of which could potentially fuel carcinogenesis. Next, we review the various pathways that contribute to the suppression of RS, and how mutations in these components lead to increased cancer incidence and/or accelerated ageing. Finally, we summarize the evidence showing that tumours with high levels of RS are dependent on a proficient RS-response, and therefore vulnerable to ATR or Chk1 inhibitors.

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PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination

Cited by 539 publications

References 65 publications

Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation

Poly(ADP-ribose) binding to Chk1 at stalled replication forks is required for S-phase checkpoint activation

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

Replication stress and cancer: It takes two to tango

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