Inhibition of the translesion synthesis polymerase REV1 exploits replication gaps as a cancer vulnerability

Nayak, Sumeet; Calvo, Jennifer A.; Cong, Ke; Peng, Min; Berthiaume, Emily A.; Jackson, Jessica; Zaino, Angela M.; Vindigni, Alessandro; Hadden, M. Kyle; Cantor, Sharon B.

doi:10.1126/sciadv.aaz7808

Cited by 95 publications

(111 citation statements)

References 73 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…Not surprisingly, TLS confers chemotherapy resistance, is a cancer adaptation, and is actively being targeted for cancer therapy (53,54). Moreover, we find that replication gaps due to BRCA deficiency is the basis for synthetic lethality to PARP inhibitors (55).…”

Section: Discussionmentioning

confidence: 83%

See 1 more Smart Citation

Replication Gaps Underlie BRCA Deficiency and Therapy Response

et al. 2021

Self Cite

View full text Add to dashboard Cite

Defects in DNA repair and the protection of stalled DNA replication forks are thought to underlie the chemosensitivity of tumors deficient in the hereditary breast cancer genes BRCA1 and BRCA2 (BRCA). Challenging this assumption are recent findings that indicate chemotherapies, such as cisplatin used to treat BRCA-deficient tumors, do not initially cause DNA double-strand breaks (DSB). Here, we show that ssDNA replication gaps underlie the hypersensitivity of BRCA-deficient cancer and that defects in homologous recombination (HR) or fork protection (FP) do not. In BRCA-deficient cells, ssDNA gaps developed because replication was not effectively restrained in response to stress. Gap suppression by either restoration of fork restraint or gap filling conferred therapy resistance in tissue culture and BRCA patient tumors. In contrast, restored FP and HR could be uncoupled from therapy resistance when gaps were present. Moreover, DSBs were not detected after therapy when apoptosis was inhibited, supporting a framework in which DSBs are not directly induced by genotoxic agents, but rather are induced from cell death nucleases and are not fundamental to the mechanism of action of genotoxic agents. Together, these data indicate that ssDNA replication gaps underlie the BRCA cancer phenotype, “BRCAness,” and we propose they are fundamental to the mechanism of action of genotoxic chemotherapies. Significance: This study suggests that ssDNA replication gaps are fundamental to the toxicity of genotoxic agents and underlie the BRCA-cancer phenotype “BRCAness,” yielding promising biomarkers, targets, and opportunities to resensitize refractory disease. See related commentary by Canman, p. 1214

show abstract

Section: Discussionmentioning

confidence: 83%

“…It will also be critical to identify gap filling mechanisms that can be targeted to restore hypersensitivity; one possible target is translesion synthesis (TLS). Indeed, CHD4 depletion elevates TLS that suppresses replication gaps (21,39,53).…”

Section: Discussionmentioning

confidence: 99%

Replication Gaps Underlie BRCA Deficiency and Therapy Response

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, since DNA damage is not induced in ER stress-adaptive cells, it remains unclear how the activity of polymerase η in stress-adaptive cells is promoted. Notably, several recent studies uncovered that PCNA was ubiquitinated even in the absence of DNA damage to recruit translesion synthesis polymerases for completion of DNA replication [ 68 , 69 , 70 ]. Thus, delayed progression of S phase and cell-cycle transition in stress adaptive cells can serve as the contributing factors to the increased activity of polymerase η, consequently accounting for the enhanced resistance of these cells to cisplatin treatment.…”

Section: Discussionmentioning

confidence: 99%

Adaptation to Endoplasmic Reticulum Stress Enhances Resistance of Oral Cancer Cells to Cisplatin by Up-Regulating Polymerase η and Increasing DNA Repair Efficiency

Chen¹,

Kawasumi

Lan

et al. 2020

IJMS

View full text Add to dashboard Cite

Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal–epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics.

show abstract

“…Distinguishing between these two possibilities will require further analysis but it has previously been shown that DNA replication genes can be up-regulated as an adaptive response to replication stress. Indeed, replication stress reduces cell fitness of cancer cells, and several adaptive mechanisms have been described including upregulation of translesion synthesis (TLS) or replisome components (Bianco et al, 2019;Nayak et al, 2020). Bianco et al, reported over-expression of Timeless, Claspin and Chk1 in various cancers, and showed that tolerating oncogene-induced replication stress was accompanied by overexpression of DDR genes and genes involved in fork protection.…”

Section: Discussionmentioning

confidence: 99%

PARG inhibition induces replication catastrophe in ovarian cancer cells with down-regulated DNA replication genes

Coulson-Gilmer

Morgan

Nelson

et al. 2020

Preprint

View full text Add to dashboard Cite

SummaryThe discovery that PARP1/2 inhibitors selectively kill BRCA mutant cells has led to a paradigm shift in the treatment of women with homologous recombination (HR)-deficient high-grade serous ovarian cancer (HGSOC), driving unprecedented improvements in progression-free and, more recently, overall survival. However, because most HGSOC cases are not HR-defective, and are therefore unlikely to benefit from PARPi-based therapies, additional strategies will be required to improve outcomes for women with HR-proficient disease. To develop novel therapeutic strategies, considerable attention is now being focused on inhibitors targeting PARG, the poly(ADP ribose) glycohydrolase that counterbalances PARP1/2 activity. Here we characterise ten ovarian cancer cell lines in response to the PARG inhibitor PDD00017273, hereafter PARGi. We demonstrate that six lines are resistant while four are sensitive, and that sensitivity correlates with several markers of persistent DNA replication stress, DNA damage and replication catastrophe, namely the accumulation of asymmetric DNA replication fibres, γH2AX and RPA foci, KAP1 and Chk1 phosphorylation, a pre-mitotic cell cycle block and, following prolonged exposure, a pan-nuclear γH2AX phenotype that indicates RPA exhaustion. We demonstrate that PARGi-sensitive cell lines have down-regulated DNA replication genes, including components of the fork protection complex, namely TIMELESS, TIPIN and CLASPIN. These observations suggest that a subset of HGSOC may respond to PARG inhibitors and that “replication stress” gene expression signature could serve as a predictive biomarker to guide the design of clinical trials.

show abstract

Inhibition of the translesion synthesis polymerase REV1 exploits replication gaps as a cancer vulnerability

Cited by 95 publications

References 73 publications

Replication Gaps Underlie BRCA Deficiency and Therapy Response

Replication Gaps Underlie BRCA Deficiency and Therapy Response

Adaptation to Endoplasmic Reticulum Stress Enhances Resistance of Oral Cancer Cells to Cisplatin by Up-Regulating Polymerase η and Increasing DNA Repair Efficiency

PARG inhibition induces replication catastrophe in ovarian cancer cells with down-regulated DNA replication genes

Contact Info

Product

Resources

About