PARP1 recruits DNA translocases to restrain DNA replication and facilitate DNA repair

Ho, Yen-Chih; Ku, Chen-Syun; Tsai, Siang-Sheng; Shiu, Jia-Lin; Jiang, Yihua; Miriam, Hui Emmanuela; Zhang, Hanwen; Chen, Yen-Tzu; Chiu, Wen‐Tai; Chang, Song-Bin; Shen, Che-Hung; Myung, Kyungjae; Chi, Peter; Liaw, Hungjiun

doi:10.1371/journal.pgen.1010545

Cited by 14 publications

(8 citation statements)

References 61 publications

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“…Previously, we have reported that CSB facilitates RAD52-mediated BIR to restart HU-induced stalled forks in S phase, as well as to repair under-replicated DNA in early mitosis following exposure to aphidicolin in S phase [18,29]. Our finding that CSB is epistatic to the MUS81-RAD52-POLD3 axis Replication stress severity has been shown to lead to different outcomes, with increased stress leading to the generation of double-strand breaks, as well as affecting the cell cycle [38]. It has been reported that a low concentration of CPT (≤25 nM) induces reversed forks without inducing the formation of DSBs [7].…”

Section: Discussionmentioning

confidence: 61%

CSB Regulates Pathway Choice in Response to DNA Replication Stress Induced by Camptothecin

Batenburg

Walker

Zhu

2023

IJMS

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Topoisomerase inhibitor camptothecin (CPT) induces fork stalling and is highly toxic to proliferating cells. However, how cells respond to CPT-induced fork stalling has not been fully characterized. Here, we report that Cockayne syndrome group B (CSB) protein inhibits PRIMPOL-dependent fork repriming in response to a low dose of CPT. At a high concentration of CPT, CSB is required to promote the restart of DNA replication through MUS81–RAD52–POLD3-dependent break-induced replication (BIR). In the absence of CSB, resumption of DNA synthesis at a high concentration of CPT can occur through POLQ–LIG3-, LIG4-, or PRIMPOL-dependent pathways, which are inhibited, respectively, by RAD51, BRCA1, and BRCA2 proteins. POLQ and LIG3 are core components of alternative end joining (Alt-EJ), whereas LIG4 is a core component of nonhomologous end joining (NHEJ). These results suggest that CSB regulates fork restart pathway choice following high-dosage CPT-induced fork stalling, promoting BIR but inhibiting Alt-EJ, NHEJ, and fork repriming. We find that loss of CSB and BRCA2 is a toxic combination to genomic stability and cell survival at a high concentration of CPT, which is likely due to accumulation of ssDNA gaps, underscoring an important role of CSB in regulating the therapy response in cancers lacking functional BRCA2.

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Section: Discussionmentioning

confidence: 61%

CSB Regulates Pathway Choice in Response to DNA Replication Stress Induced by Camptothecin

Batenburg

Walker

Zhu

2023

IJMS

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“…Recent advances have revealed that PARP1 functions as a sensor of replication stress and promotes the formation of reversed forks to prevent the collapse of forks into DSBs, in addition to its role in SSB repair ( 9 , 10 , 49–51 ). Since APLF interacts with PARP1, we investigate whether APLF is also involved in fork stability during replication stress.…”

Section: Resultsmentioning

confidence: 99%

“…The depletion of BRCA1, BRCA2, RAD51 or FANCD2 results in fork degradation mediated by the MRE11 nuclease. Recent advances have revealed that PARP1 is a sensor of replication stress that recruits DNA translocases, including HLTF, SHPRH, ZRANB3 and SMARCAL1, to convert stalled forks into reversed forks, and this process also depends on RAD51 recombinase ( 4 , 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance

Wu,

Shiu,

et al. 2024

Nucleic Acids Research

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Replication stress converts the stalled forks into reversed forks, which is an important protection mechanism to prevent fork degradation and collapse into poisonous DNA double-strand breaks (DSBs). Paradoxically, the mechanism also acts in cancer cells to contribute to chemoresistance against various DNA-damaging agents. PARP1 binds to and is activated by stalled forks to facilitate fork reversal. Aprataxin and polynucleotide kinase/phosphatase-like factor (APLF) binds to PARP1 through the poly(ADP-ribose) zinc finger (PBZ) domain and is known to be involved in non-homologous end joining (NHEJ). Here, we identify a novel function of APLF involved in interstrand DNA crosslink (ICL) repair and fork protection. We demonstrate that PARP1 activity facilitates the APLF recruitment to stalled forks, enabling the FANCD2 recruitment to stalled forks. The depletion of APLF sensitizes cells to cisplatin, impairs ICL repair, reduces the FANCD2 recruitment to stalled forks, and results in nascent DNA degradation by MRE11 nucleases. Additionally, cisplatin-resistant cancer cells show high levels of APLF and homologous recombination-related gene expression. The depletion of APLF sensitizes cells to cisplatin and results in fork instability. Our results reveal the novel function of APLF to facilitate ICL repair and fork protection, thereby contributing to cisplatin-resistant phenotypes of cancer cells.

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“…As a key contributor to the DNA damage response, PARP1 also participates in the regulation of stalled replication fork reversal and restart. It is proposed that PARP1 binds to stalled replication forks and recruits the translocases SMARCAL1, ZRANB3, and HLTF to initiate fork reversal [ 79 ]. The PARylation activity of PARP1 further prevents the RECQ1-dependent premature restart of reversed forks [ 80 ].…”

Section: Ubiquitination Coordinates a Concerted Response At Stalled R...mentioning

confidence: 99%

Implications of ubiquitination and the maintenance of replication fork stability in cancer therapy

Xia,

Zhu,

Wang

et al. 2023

Bioscience Reports

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DNA replication forks are subject to intricate surveillance and strict regulation by sophisticated cellular machinery. Such close regulation is necessary to ensure the accurate duplication of genetic information and to tackle the diverse endogenous and exogenous stresses that impede this process. Stalled replication forks are vulnerable to collapse, which is a major cause of genomic instability and carcinogenesis. Replication stress responses, which are organized via a series of coordinated molecular events, stabilize stalled replication forks and carry out fork reversal and restoration. DNA damage tolerance and repair pathways such as homologous recombination and Fanconi anemia also contribute to replication fork stabilization. The signaling network that mediates the transduction and interplay of these pathways is regulated by a series of post-translational modifications, including ubiquitination, which affects the activity, stability, and interactome of substrates. In particular, the ubiquitination of replication protein A and proliferating cell nuclear antigen at stalled replication forks promotes the recruitment of downstream regulators. In this review, we describe the ubiquitination-mediated signaling cascades that regulate replication fork progression and stabilization. In addition, we discuss the targeting of replication fork stability and ubiquitination system components as a potential therapeutic approach for the treatment of cancer.

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PARP1 recruits DNA translocases to restrain DNA replication and facilitate DNA repair

Cited by 14 publications

References 61 publications

CSB Regulates Pathway Choice in Response to DNA Replication Stress Induced by Camptothecin

CSB Regulates Pathway Choice in Response to DNA Replication Stress Induced by Camptothecin

APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance

Implications of ubiquitination and the maintenance of replication fork stability in cancer therapy

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