Unrepaired base excision repair intermediates in template DNA strands trigger replication fork collapse and PARP inhibitor sensitivity DOI Creative Commons
Almudena Serrano-Benítez, Sophie E. Wells, Lylah Drummond‐Clarke

и другие.

The EMBO Journal, Год журнала: 2023, Номер 42(18)

Опубликована: Июль 26, 2023

Abstract DNA single‐strand breaks (SSBs) disrupt replication and induce chromosome breakage. However, whether SSBs breakage when present behind forks or ahead of is unclear. To address this question, we exploited an exquisite sensitivity SSB repair‐defective human cells lacking PARP activity XRCC1 to the thymidine analogue 5‐chloro‐2′‐deoxyuridine (CldU). We show that incubation with CldU in these results breakage, sister chromatid exchange, cytotoxicity by a mechanism depends on S phase uracil glycosylase (UNG). Importantly, incorporation one cell cycle cytotoxic only during following cycle, it template DNA. In agreement this, while UNG induces both nascent strands forks, latter trigger fork collapse Finally, BRCA‐defective are hypersensitive CldU, either alone and/or combination inhibitor, suggesting may have clinical utility.

Язык: Английский

Platinum(IV) Complexes as Inhibitors of STAT3 and Regulators of the Tumor Microenvironment To Control Breast Cancer DOI
Linxiang Cai, Ying Wang, Hanhua Chen

и другие.

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(16), С. 11351 - 11364

Опубликована: Авг. 14, 2023

Interplay between breast cancer (BC) cells and the tumor microenvironment (TME) influences outcome of treatment. Aberrant activation signal transducer activator transcription 3 (STAT3) promotes interaction causes immunosuppression drug resistance. Platinum(IV) complexes SPP DPP bearing pterostilbene-derived axial ligand(s) were synthesized to inhibit JAK2-STAT3 pathway in BC regulate TME. These exerted remarkable antiproliferative activity against triple-negative cells, suppressed expression phosphorylated STAT3 STAT3-related cyclooxygenase-2 IL-6, activated caspase-3 cleaved poly ADP-ribose polymerase, preventing repair DNA lesions inducing apoptosis. Furthermore, promoted maturation antigen presentation dendritic repressed proliferation differentiation myeloid-derived suppressor regulatory T facilitated expansion cells. As a consequence, showed excellent anticancer with almost no general toxicity vivo as potential chemoimmunotherapeutic agent.

Язык: Английский

Процитировано

24
Unprocessed genomic uracil as a source of DNA replication stress in cancer cells DOI
Sneha Saxena, Christopher S. Nabel, Turner W. Seay

и другие.

Molecular Cell, Год журнала: 2024, Номер 84(11), С. 2036 - 2052.e7

Опубликована: Апрель 29, 2024

Язык: Английский

Процитировано

14
USP1-dependent nucleolytic expansion of PRIMPOL-generated nascent DNA strand discontinuities during replication stress DOI Creative Commons
Alexandra Nusawardhana,

Lindsey M Pale,

Claudia M. Nicolae

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер 52(5), С. 2340 - 2354

Опубликована: Янв. 5, 2024

DNA replication stress-induced fork arrest represents a significant threat to genomic integrity. One major mechanism of restart involves repriming downstream the arrested by PRIMPOL, leaving behind single-stranded (ssDNA) gap. Accumulation nascent strand ssDNA gaps has emerged as possible determinant cellular hypersensitivity genotoxic agents in certain genetic backgrounds such BRCA deficiency, but how are converted into cytotoxic structures is still unclear. Here, we investigate processing PRIMPOL-dependent upon stress induced hydroxyurea and cisplatin. We show that generated PRIMPOL-overexpressing cells expanded 3'-5' direction MRE11 exonuclease, 5'-3' EXO1 exonuclease. This bidirectional exonucleolytic gap expansion ultimately promotes their conversion DSBs. moreover identify de-ubiquitinating enzyme USP1 critical regulator PRIMPOL-generated gaps. accumulation during S-phase, nucleases. activity linked its role PCNA, suggesting PCNA ubiquitination prevents replication. Finally, depletion suppresses DSB formation cells, highlighting an unexpected for promoting instability under these conditions.

Язык: Английский

Процитировано

13
BRCAness, DNA gaps, and gain and loss of PARP inhibitor–induced synthetic lethality DOI Creative Commons
Xin Li, Lee Zou

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(14)

Опубликована: Июль 14, 2024

Mutations in the tumor-suppressor genes BRCA1 and BRCA2 resulting BRCA1/2 deficiency are frequently identified breast, ovarian, prostate, pancreatic, other cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, providing an effective biomarker-guided strategy for targeted therapy. However, a substantial fraction of patients carrying mutations do not respond to PARPis, most develop resistance PARPis over time, highlighting major obstacle PARPi therapy clinic. Recent studies have revealed that changes specific functional defects cells, particularly their suppressing protecting single-stranded DNA gaps, contribute gain or loss PARPi-induced lethality. These findings only shed light on mechanism action but also lead revised models explain how BRCA-deficient cells. Furthermore, new mechanistic principles sensitivity emerged from these studies, generating potentially useful guidelines predicting response design therapies overcoming resistance. In this Review, we will discuss recent put them context with classic views aiming stimulate development therapeutic strategies overcome improve

Язык: Английский

Процитировано

13
FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells DOI Creative Commons
Ke Cong, Nathan J. MacGilvary, Silviana Lee

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 23, 2024

The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in creating single-stranded DNA gaps and inducing sensitivity requires the FANCJ helicase. Yet, how relates to PARP1 inhibition or trapping, which contribute PARPi toxicity, remains unclear. Here, we find hinges on S-phase activity, is reduced deficient cells as G-quadruplexes sequester MSH2. Additionally, loss FANCJ-MLH1 interaction diminishes activity; however, depleting MSH2 reinstates gaps. Indicating sequestered trapped are distinct, increases resistance susceptible trapping. However, with BRCA1 deficiency, mirrors inhibition, detrimental commonality being activity. These insights underline crucial role activity during replication emphasize importance understanding drug mechanisms for enhancing therapeutic response.

Язык: Английский

Процитировано

12
PARPi, BRCA, and gaps: controversies and future research DOI Creative Commons
Diego Dibitetto, Carmen A. Widmer, Sven Rottenberg

и другие.

Trends in cancer, Год журнала: 2024, Номер 10(9), С. 857 - 869

Опубликована: Июль 14, 2024

In recent years, various poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been approved for the treatment of several cancers to target vulnerability homologous recombination (HR) deficiency (e.g., due BRCA1/2 dysfunction). this review we analyze ongoing debates and breakthroughs in use PARPis BRCA1/2-deficient cancers, juxtaposing 'double-strand break (DSB)' 'single-stranded DNA (ssDNA) gap' models synthetic lethality induced by PARPis. We spotlight complexity interaction, highlighting emerging research on role theta (POLθ) ssDNA gaps shaping therapy responses. scrutinize clinical ramifications these findings, especially concerning PARPi efficacy resistance mechanisms, underscoring heterogeneity BRCA-mutated tumors urgent need advanced bridge gap between laboratory patient outcomes.

Язык: Английский

Процитировано

10
PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair DOI Creative Commons
Christina Andronikou, Kamila Burdová, Diego Dibitetto

и другие.

The EMBO Journal, Год журнала: 2024, Номер 43(6), С. 1015 - 1042

Опубликована: Фев. 15, 2024

Abstract Targeting poly(ADP-ribose) glycohydrolase (PARG) is currently explored as a therapeutic approach to treat various cancer types, but we have poor understanding of the specific genetic vulnerabilities that would make cells susceptible such tailored therapy. Moreover, identification interest for targeting BRCA2;p53-deficient tumors acquired resistance polymerase inhibitors (PARPi) through loss PARG expression. Here, by performing whole-genome CRISPR/Cas9 drop-out screens, identify genes involved in DNA repair be essential survival PARG;BRCA2;p53-deficient cells. In particular, our findings reveal EXO1 and FEN1 major synthetic lethal interactors loss. We provide evidence compromised replication fork progression, single-strand break repair, Okazaki fragment processing cells, alterations exacerbate effects EXO1/FEN1 inhibition become this context. Since sensitivity dependent on BRCA2 defects, propose target PARPi-resistant lost activity. may useful strategy enhancing effect homologous recombination-deficient tumors.

Язык: Английский

Процитировано

9
The TIMELESS and PARP1 interaction suppresses replication-associated DNA gap accumulation DOI Creative Commons
Joanne Saldanha, Julie Rageul,

Jinal A Patel

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер 52(11), С. 6424 - 6440

Опубликована: Май 27, 2024

Abstract TIMELESS (TIM) in the fork protection complex acts as a scaffold of replisome to prevent its uncoupling and ensure efficient DNA replication progression. Nevertheless, underlying basis for coordinating leading lagging strand synthesis limit single-stranded (ssDNA) exposure remains elusive. Here, we demonstrate that acute degradation TIM at ongoing forks induces accumulation ssDNA gaps stemming from defective Okazaki fragment (OF) processing. Cells devoid fail support poly(ADP-ribosyl)ation necessary backing up canonical OF processing mechanism mediated by LIG1 FEN1. Consequently, recruitment XRCC1, known effector PARP1-dependent single-strand break repair, post-replicative behind is impaired. Physical disruption TIM–PARP1 phenocopies rapid loss TIM, indicating interaction critical activation this compensatory pathway. Accordingly, combined deficiency FEN1 leads synergistic damage cytotoxicity. We propose essential engagement PARP1 coordinate with Our study identifies synthetic lethal target enzymes can be exploited cancer therapy.

Язык: Английский

Процитировано

9
CHK1 inhibitor induced PARylation by targeting PARG causes excessive replication and metabolic stress and overcomes chemoresistance in ovarian cancer DOI Creative Commons
Ganesh Acharya,

Chinnadurai Mani,

Naresh Sah

и другие.

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Июнь 11, 2024

Abstract Chemoresistance contributes to the majority of deaths in women with ovarian cancer (OC). Altered DNA repair and metabolic signaling is implicated mediating therapeutic resistance. damage checkpoint kinase 1 (CHK1) integrates cell cycle replicating cells, its inhibition causes replication stress, deficiency dysregulation. We observed elevated Poly-ADP-ribosylation (PAR) proteins (PARylation) subsequent decrease cellular NAD + levels OC cells treated CHK1 inhibitor prexasertib, indicating activation dependent enzymes poly-ADP-ribose polymerases (PARP1/2). While multiple PARP inhibitors are clinical use treating OC, tumor resistance these drugs highly imminent. reasoned that dePARylation by targeting Poly (ADP-ribose) glycohydrolase (PARG) would disrupt crosstalk overcome chemoresistance. Although PARG (PARGi) trapped PARylation activated CHK1, it did not cause any significant death. However, deficient were hypersensitive PARGi, suggesting a role for protection cells. Correspondingly, combination exhibited excessive stress-mediated lesions, dysregulation, mitotic catastrophe compared individual drugs. Interestingly, increased treatment resulted depletion levels. These decreased also paralleled reduced aldehyde dehydrogenase (ALDH) activity, which requires maintain stem Furthermore, prexasertib PARGi combinations synergistic death including an isogenic chemoresistant line 3D organoid models primary patient-derived lines. Collectively, our data highlight novel between metabolism involving stress -dependent PARylation, suggest therapy chemoresistance OC.

Язык: Английский

Процитировано

8
Overview of the epigenetic/cytotoxic dual-target inhibitors for cancer therapy DOI

Hailiu Liang,

Shuqing Li, Xiaopeng Peng

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 285, С. 117235 - 117235

Опубликована: Янв. 5, 2025

Язык: Английский

Процитировано

1