Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death

Houl, Jerry H.; Ye, Z.; Brosey, Chris A.; Balapiti-Modarage, L.P.F.; Namjoshi, Sarita; Bacolla, Albino; Laverty, Daniel J.; Walker, Brandon L.; Pourfarjam, Yasin; Warden, L.S.; Chinnam, Naga Babu; Moiani, Davide; Stegeman, Roderick A.; Chen, Mei-Kuang; Hung, Mien‐Chie; Nagel, Zachary D.; Ellenberger, Tom; Kim, I.K.; Jones, Darin E.; Ahmed, Zamal; Tainer, John A.

doi:10.1038/s41467-019-13508-4

Cited by 83 publications

(63 citation statements)

References 69 publications

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“…cancer cells . However, PARG depletion did not show synthetic lethality with BRCA1 mutations in different cancer cell lines (Noll et al 2016), the PARG inhibitor JA2131 efficiently killed BRCA-proficient cancer cells (Houl et al 2019), and only one out of six tested ovarian cancer cells with BRCA1/2 mutations showed sensitivity to PARG inhibition with PDD00017273 (Pillay et al 2019). Instead, synthetic lethal interactions with the PARG inhibitor PDD00017273 involve replication-associated genes such as TIMELESS, HUS1, and RFC2 ( Fig.…”

Section: Synthetic Lethality Between Parp or Parg Inhibitors And Genomentioning

confidence: 97%

“…The naphthalen-type PARG inhibitor COH34 is a potent, specific, and cell-permeable inhibitor with a terminal half-life of 3.9 h, and may thus prove a good candidate for clinical studies . Chemical library screening identified thioxanthine/methylxanthine derivatives JA2-4 and JA2131 as potent, specific, cell-permeable, and cell-active PARG inhibitors, which are also likely to show good bioavailability given their structural similarity with caffeine (Houl et al 2019). PARG inhibitors compete with PAR for the PARG active site by occupying the subsite normally occupied by the adenine moiety of ADP-ribose ( Fig.…”

Section: Molecular Mechanisms Of Parp and Parg Inhibitorsmentioning

confidence: 99%

“…PARG inhibitors compete with PAR for the PARG active site by occupying the subsite normally occupied by the adenine moiety of ADP-ribose ( Fig. 1; James et al 2016;Chen and Yu 2019;Houl et al 2019).…”

Section: Molecular Mechanisms Of Parp and Parg Inhibitorsmentioning

confidence: 99%

“…PARG depletion or inhibition slows down replication forks, causes accumulation of reversed forks and ssDNA gaps, and prevents fork restart through suppression of the RECQ1 helicase ( Fig. 6; Illuzzi et al 2014;Ray Chaudhuri et al 2015;Gravells et al 2017;Houl et al 2019;Pillay et al 2019). This causes cell cycle stalling in the S/G2 phase, accumulation of ssDNA as judged by RPA foci, and accumulation of DNA damage, as indicated by pan-nuclear γH2AX staining (Illuzzi et al 2014;Pillay et al 2019).…”

Section: Amplifying Genomic Instability With Parp and Parg Inhibitorsmentioning

confidence: 99%

“…Prolonged exposure of PARG-depleted cells to replication stress results in the loss of RPA foci, indicating RPA exhaustion due to replication stress-induced formation of ssDNA-a concept known as replication catastrophe (Illuzzi et al 2014;Toledo et al 2017). PARP1 or PARG depletion or inhibition sensitize cells to DNAdamaging agents and cause increased DNA damage levels due to decreased HR efficiency (Rottenberg et al 2008;Ame et al 2009;Min et al 2010;Shirai et al 2013;Murai et al 2014b;Dréan et al 2016;James et al 2016;Gravells et al 2018;Houl et al 2019). Collectively, loss or inhibition of PARP1 or PARG destabilize replication forks and cause fork breakage, particularly under conditions of HR deficiency, oxidative and replication stress, or exogenous DNA damage.…”

Section: Amplifying Genomic Instability With Parp and Parg Inhibitorsmentioning

confidence: 99%

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PARP and PARG inhibitors in cancer treatment

2020

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Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful example of precision medicine as the first drugs targeting DNA damage response to have entered the clinic. PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer. PARP inhibitors destabilize replication forks through PARP DNA entrapment and induce cell death through replication stress-induced mitotic catastrophe. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability. Here I provide an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. I highlight clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discuss the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy.

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Section: Synthetic Lethality Between Parp or Parg Inhibitors And Genomentioning

confidence: 97%

Section: Molecular Mechanisms Of Parp and Parg Inhibitorsmentioning

confidence: 99%

Section: Molecular Mechanisms Of Parp and Parg Inhibitorsmentioning

confidence: 99%

Section: Amplifying Genomic Instability With Parp and Parg Inhibitorsmentioning

confidence: 99%

Section: Amplifying Genomic Instability With Parp and Parg Inhibitorsmentioning

confidence: 99%

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PARP and PARG inhibitors in cancer treatment

2020

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Exploring the genetic space of the DNA damage response for cancer therapy through CRISPR‐based screens

Wilson

Loizou

2022

Molecular Oncology

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The concepts of synthetic lethality and viability have emerged as powerful approaches to identify vulnerabilities and resistances within the DNA damage response for the treatment of cancer. Historically, interactions between two genes have had a longstanding presence in genetics and have been identified through forward genetic screens that rely on the molecular basis of the characterized phenotypes, typically caused by mutations in single genes. While such complex genetic interactions between genes have been studied extensively in model organisms, they have only recently been prioritized as therapeutic strategies due to technological advancements in genetic screens. Here, we discuss synthetic lethal and viable interactions within the DNA damage response and present how CRISPR-based genetic screens and chemical compounds have allowed for the systematic identification and targeting of such interactions for the treatment of cancer.

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Targeting DNA repair pathway in cancer: Mechanisms and clinical application

Wang

Chen

2021

MedComm

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Over the last decades, the growing understanding on DNA damage response (DDR) pathways has broadened the therapeutic landscape in oncology. It is becoming increasingly clear that the genomic instability of cells resulted from deficient DNA damage response contributes to the occurrence of cancer. One the other hand, these defects could also be exploited as a therapeutic opportunity, which is preferentially more deleterious in tumor cells than in normal cells. An expanding repertoire of DDR‐targeting agents has rapidly expanded to inhibitors of multiple members involved in DDR pathways, including PARP, ATM, ATR, CHK1, WEE1, and DNA‐PK. In this review, we sought to summarize the complex network of DNA repair machinery in cancer cells and discuss the underlying mechanism for the application of DDR inhibitors in cancer. With the past preclinical evidence and ongoing clinical trials, we also provide an overview of the history and current landscape of DDR inhibitors in cancer treatment, with special focus on the combination of DDR‐targeted therapies with other cancer treatment strategies.

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Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death

Cited by 83 publications

References 69 publications

PARP and PARG inhibitors in cancer treatment

PARP and PARG inhibitors in cancer treatment

Exploring the genetic space of the DNA damage response for cancer therapy through CRISPR‐based screens

Targeting DNA repair pathway in cancer: Mechanisms and clinical application

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