A Distinct Replication Fork Protection Pathway Connects Fanconi Anemia Tumor Suppressors to RAD51-BRCA1/2

Schlacher, Katharina; Wu, Hong Gyun; Jasin, Maria

doi:10.1016/j.ccr.2012.05.015

Cited by 767 publications

(1,021 citation statements)

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“…The role of PTEN in replication fork stabilization represents a novel mechanism for tumor suppression. It has been reported that some well known factors such as RAD51, BRCA1/2 and FANCD2 participate in replication fork protection and are associated with the maintenance of genomic integrity [20,33]. PTEN is able to regulate RAD51 [8], thus it is possible that the PTEN-RPA1 mechanism we describe here is mechanistically linked to the RAD51-BRCA1/2 pathway.…”

Section: Discussionmentioning

confidence: 73%

PTEN regulates RPA1 and protects DNA replication forks

Wang

et al. 2015

Cell Res

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Tumor suppressor PTEN regulates cellular activities and controls genome stability through multiple mechanisms. In this study, we report that PTEN is necessary for the protection of DNA replication forks against replication stress. We show that deletion of PTEN leads to replication fork collapse and chromosomal instability upon fork stalling following nucleotide depletion induced by hydroxyurea. PTEN is physically associated with replication protein A 1 (RPA1) via the RPA1 C-terminal domain. STORM and iPOND reveal that PTEN is localized at replication sites and promotes RPA1 accumulation on replication forks. PTEN recruits the deubiquitinase OTUB1 to mediate RPA1 deubiquitination. RPA1 deletion confers a phenotype like that observed in PTEN knockout cells with stalling of replication forks. Expression of PTEN and RPA1 shows strong correlation in colorectal cancer. Heterozygous disruption of RPA1 promotes tumorigenesis in mice. These results demonstrate that PTEN is essential for DNA replication fork protection. We propose that RPA1 is a target of PTEN function in fork protection and that PTEN maintains genome stability through regulation of DNA replication.

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Section: Discussionmentioning

confidence: 73%

PTEN regulates RPA1 and protects DNA replication forks

Wang

et al. 2015

Cell Res

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“…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). Whether the role of HR factors in the face of endogenous or exogenous replication stress is related to replication fork remodelling will be the subject of intense studies in the near future.…”

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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“…8,9 Together with the central Fanconi anemia protein FANCD2, BRCA1, BRCA2 and Rad51 protect hydroxyurea-stalled replication forks from processing by the MRE11 nuclease. [23][24][25] BRCA1 also promotes the processing of replication forks stalled by UV irradiation. 26 We found that BRCA1, BRCA2 and Rad51 are required for efficient STGC at Tus/Ter stalled replication forks, whereas loss of BRCA1 or BRCA2 led to a paradoxical increase in aberrant "long tract" gene conversions (LTGCs) at Tus/Ter stalled forks.…”

Section: Introductionmentioning

confidence: 99%

Spatial separation of replisome arrest sites influences homologous recombination quality at a Tus/Ter-mediated replication fork barrier

Willis

Scully

2016

Cell Cycle

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The Escherichia coli replication fork arrest complex Tus/Ter mediates site-specific replication fork arrest and homologous recombination (HR) on a mammalian chromosome, inducing both conservative "short tract" gene conversion (STGC) and error-prone "long tract" gene conversion (LTGC) products. We showed previously that bidirectional fork arrest is required for the generation of STGC products at Tus/Ter-stalled replication forks and that the HR mediators BRCA1, BRCA2 and Rad51 mediate STGC but suppress LTGC at Tus/Ter-arrested forks. Here, we report the impact of Ter array length on Tus/Ter-induced HR, comparing HR reporters containing arrays of 6, 9, 15 or 21 Ter sites-each targeted to the ROSA26 locus of mouse embryonic stem (ES) cells. Increasing Ter copy number within the array beyond 6 did not affect the magnitude of Tus/Ter-induced HR but biased HR in favor of LTGC. A "lock"-defective Tus mutant, F140A, known to exhibit higher affinity than wild type (wt)Tus for duplex Ter, reproduced these effects. In contrast, increasing Ter copy number within the array reduced HR induced by the I-SceI homing endonuclease, but produced no consistent bias toward LTGC. Thus, the mechanisms governing HR at Tus/Ter-arrested replication forks are distinct from those governing HR at an enzyme-induced chromosomal double strand break (DSB). We propose that increased spatial separation of the 2 arrested forks encountering an extended Tus/Ter barrier impairs the coordination of DNA ends generated by the processing of the stalled forks, thereby favoring aberrant LTGC over conservative STGC.

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A Distinct Replication Fork Protection Pathway Connects Fanconi Anemia Tumor Suppressors to RAD51-BRCA1/2

Cited by 767 publications

References 44 publications

PTEN regulates RPA1 and protects DNA replication forks

PTEN regulates RPA1 and protects DNA replication forks

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

Spatial separation of replisome arrest sites influences homologous recombination quality at a Tus/Ter-mediated replication fork barrier

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