DNA replication stress and emerging prospects for PARG inhibitors in ovarian cancer therapy

Pillay, Nisha; Brady, Rosie M; Dey, Malini; Morgan, Robert D.; Taylor, Stephen S.

doi:10.1016/j.pbiomolbio.2021.01.004

Cited by 21 publications

(10 citation statements)

References 121 publications

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“…The results of early studies indicated that defective DNA repair pathways and DNA replication stress would result in enhanced sensitivity to PARG inhibitor, PDD00017273 (PARGi) 25–27, 38, 39 . To further define the key DDR pathways that are important for cellular response to PARGi, we performed CRISPR screening using our homemade DDR sgRNA library, which targets approximately 360 genes involved in various DDR pathways 34 .…”

Section: Resultsmentioning

confidence: 99%

DePARylation is critical for S phase progression and cell survival

Nie

Wang

Liu

et al. 2023

Preprint

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Poly(ADP-ribose)ylation or PARylation by PAR polymerase 1 (PARP1) and dePARylation by poly(ADP-ribose) glycohydrolase (PARG) are equally important for the dynamic regulation of DNA damage response. PARG, the most active dePARylation enzyme, is recruited to sites of DNA damage via pADPr-dependent and PCNA-dependent mechanisms. Targeting dePARylation is considered an alternative strategy to overcome PARP inhibitor resistance. However, precisely how dePARylation functions in normal unperturbed cells remains elusive. To address this challenge, we conducted multiple CRISPR screens and revealed that dePARylation of S phase pADPr by PARG is essential for cell viability. Loss of dePARylation activity initially induced S phase-specific pADPr signaling, which resulted from unligated Okazaki fragments and eventually led to uncontrolled pADPr accumulation and PARP1/2-dependent cytotoxicity. Moreover, we demonstrated that proteins involved in Okazaki fragment ligation and/or base excision repair regulate pADPr signaling and cell death induced by PARG inhibition. In addition, we determined that PARG expression is critical for cellular sensitivity to PARG inhibition. Additionally, we revealed that PARG is essential for cell survival by suppressing pADPr. Collectively, our data not only identify an essential role for PARG in normal proliferating cells but also provide a potential biomarker for the further development of PARG inhibitors in cancer therapy.

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Section: Resultsmentioning

confidence: 99%

DePARylation is critical for S phase progression and cell survival

Nie

Wang

Liu

et al. 2023

Preprint

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“…In this case, CCDC6 depletion might worsen DNA damage by preventing HR repair. By slowing down replication forks, accumulating inverted forks and ssDNA gaps, and inhibiting the RECQ1 helicase, PARG depletion or inhibition, on the other hand, results in cell cycle stalling in the S/G2 phase [24][25][26][59][60][61][62].…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, 20% of BRCA1/2-mutated ovarian malignancies do not respond to PARPi [20][21][22][23], highlighting the urgent need for new treatment approaches for inherently or acquired resistant tumours. The inhibition of poly(ADP-ribose) glycohydrolase (PARG), one of the enzymes necessary for reversing PARylation processes, shows promise as a treatment strategy for PARPiresistant HGSOC [24][25][26]. It should be emphasised that HGSOC's susceptibility to PARPi and PARG inhibitors (PARGi) are mutually exclusive, which raises the possibility of a novel treatment approach for ovarian malignancies that are PARPi-resistant [24].…”

Section: Introductionmentioning

confidence: 99%

The disruption of the CCDC6 – PP4 axis induces a BRCAness like phenotype and sensitivity to PARP inhibitors in high-grade serous ovarian carcinoma

Morra

Merolla

Damia

et al. 2022

J Exp Clin Cancer Res

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Background Treatment with PARP inhibitors (PARPi) is primarily effective against high-grade serous ovarian cancers (HGSOC) with BRCA1/2 mutations or other deficiencies in homologous recombination (HR) repair mechanisms. However, resistance to PARPi frequently develops, mostly as a result of BRCA1/2 reversion mutations. The tumour suppressor CCDC6 is involved in HR repair by regulating the PP4c phosphatase activity on γH2AX. In this work, we reported that in ovarian cancer cells, a physical or functional loss of CCDC6 results synthetic lethal with the PARP-inhibitors drugs, by affecting the HR repair. We also unravelled a role for CCDC6 as predictive marker of PARPi sensitivity in ovarian cancer, and the impact of CCDC6 downregulation in overcoming PARPi resistance in these tumours. Methods A panel of HGSOC cell lines (either BRCA-wild type or mutant) were treated with PARPi after CCDC6 was attenuated by silencing or by inhibiting USP7, a CCDC6-deubiquitinating enzyme, and the effects on cell survival were assessed. At the cellular and molecular levels, the processes underlying the CCDC6-dependent modification of drugs’ sensitivity were examined. Patient-derived xenografts (PDXs) were immunostained for CCDC6, and the expression of the protein was analysed statistically after digital or visual means. Results HGSOC cells acquired PARPi sensitivity after CCDC6 depletion. Notably, CCDC6 downregulation restored the PARPi sensitivity in newly generated or spontaneously resistant cells containing either wild type- or mutant-BRCA2. When in an un-phosphorylated state, the CCDC6 residue threonine 427 is crucial for effective CCDC6-PP4 complex formation and PP4 sequestration, which maintains high γH2AX levels and effective HR. Remarkably, the PP4-dependent control of HR repair is influenced by the CCDC6 constitutively phosphorylated mutant T427D or by the CCDC6 loss, favouring PARPi sensitivity. As a result, the PP4 regulatory component PP4R3α showed to be essential for both the activity of the PP4 complex and the CCDC6 dependent PARPi sensitivity. It's interesting to note that immunohistochemistry revealed an intense CCDC6 protein staining in olaparib-resistant HGSOC cells and PDXs. Conclusions Our findings suggest that the physical loss or the functional impairment of CCDC6 enhances the PP4c complex activity, which causes BRCAness and PARPi sensitivity in HGSOC cells. Moreover, CCDC6 downregulation might overcome PARPi resistance in HGSOCs, thus supporting the potential of targeting CCDC6 by USP7 inhibitors to tackle PARPi resistance.

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“…9 Taking into account the involvement of PARG in PARP regulation, researchers have investigated the role of PARG in cancer. [10][11][12][13][14] PARG inhibitors have antitumor effects in solid tumors, such as ovarian cancer and pancreatic cancer, [15][16][17] and they have been used either alone or in combination with DNAdamaging agents or radiotherapy to treat cancer in vivo or in vitro. 18,19 Experiments have shown that PARG has a relationship with cancer development and that overexpression of PARG in some tumors is related to poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

The role of poly (ADP‐ribose) glycohydrolase in phosphatase and tensin homolog deficiency endometrial cancer

Sun

Shi

Liu

et al. 2023

J of Obstet and Gynaecol

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To explore the relationship between poly(ADP-ribose) glycohydrolase (PARG) and the occurrence, development, and prognosis of endometrial carcinoma (EC), and investigate whether the PARG inhibitor PDD0017273 could increase the sensitivity of EC cells to cisplatin. Methods: The expression of PARG, phosphatase and tensin homolog (PTEN), and p53 in normal endometrial tissues (NE), endometrial hyperplasia without atypia (EH), atypical endometrial hyperplasia (AH), and EC was detected by immunohistochemistry. AN3CA EC cells with PTEN deficiency were treated with different cisplatin and PDD0017273, alone or in combination. Cell proliferation was detected by MTT method, apoptosis was detected by flow cytometry, and the expression of PARG in EC cells after treatment with different drugs was detected by western blot and immunohistochemistry. Results: Expression of PARG in NE, EH, AH, and EC increased gradually. In addition, compared with low PARG expression in PTEN-positive EC, patients who had high PARG expression in PTEN-negative EC had more advanced clinical stages (r = À0.399, p = 0.032) and shorter overall survival time (p = 0.037). A dose of 40 μM PDD0017273 effectively inhibited PARG expression, increased the sensitivity of AN3CA cells to cisplatin. Conclusions: The findings suggest that PARG overexpression is a promising immunohistochemical marker to predict the occurrence and prognosis of EC. Moreover, PARG inhibition produced antitumor effects and increased the sensitivity of EC cells with PTEN deficiency to cisplatin.

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DNA replication stress and emerging prospects for PARG inhibitors in ovarian cancer therapy

Cited by 21 publications

References 121 publications

DePARylation is critical for S phase progression and cell survival

DePARylation is critical for S phase progression and cell survival

The disruption of the CCDC6 – PP4 axis induces a BRCAness like phenotype and sensitivity to PARP inhibitors in high-grade serous ovarian carcinoma

The role of poly (ADP‐ribose) glycohydrolase in phosphatase and tensin homolog deficiency endometrial cancer

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