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

Mechanisms of PARP1 inhibitor resistance and their implications for cancer treatment DOI

Lindsey M. Jackson,

George‐Lucian Moldovan

NAR Cancer, Год журнала: 2022, Номер 4(4)

Опубликована: Сен. 28, 2022

The discovery of synthetic lethality as a result the combined loss PARP1 and BRCA has revolutionized treatment DNA repair-deficient cancers. With development PARP inhibitors, patients displaying germline or somatic mutations in BRCA1 BRCA2 were presented with novel therapeutic strategy. However, large subset do not respond to inhibitors. Furthermore, many those who eventually acquire resistance. As such, combating de novo acquired resistance inhibitors remains an obstacle achieving durable responses patients. In this review, we touch on some key mechanisms inhibitor resistance, including restoration homologous recombination, replication fork stabilization suppression single-stranded gap accumulation, well address approaches for overcoming

Язык: Английский

Процитировано

31
PET imaging of PARP expression using 68Ga-labelled inhibitors DOI Creative Commons
Xiangwei Wang, Wei Liu, Ké Li

и другие.

European Journal of Nuclear Medicine and Molecular Imaging, Год журнала: 2023, Номер 50(9), С. 2606 - 2620

Опубликована: Май 5, 2023

Abstract Purpose Imaging the PARP expression using 18 F probes has been approved in clinical trials. Nevertheless, hepatobiliary clearance of both hindered their application monitoring abdominal lesions. Our novel 68 Ga-labelled aim for fewer signals while ensuring targeting by optimizing pharmacokinetic properties radioactive probes. Methods Three targeted were designed, synthesized, and evaluated based on inhibitor Olaparib. These radiotracers assessed vitro vivo. Results Precursors that did not lose binding affinity then labelled with Ga high radiochemical purity (> 97%). The stable. Due to increased PARP-1 SK-OV-3 cells, uptake three cells was significantly greater than A549 cells. PET/CT imaging models indicated tumor Ga-DOTA-Olaparib (0.5 h: 2.83 ± 0.55%ID/g; 1 2.37 0.64%ID/g) higher other radiotracers. There a significant difference T/M (tumor-to-muscle) ratios between unblocked blocked groups as calculated from images (4.07 1.01 vs. 1.79 0.45, P = 0.0238 < 0.05). Tumor autoradiography revealed accumulation tissues, further confirming above data. confirmed immunochemistry. Conclusion As first inhibitor, displayed stability quick model. This compound is thus promising agent can be used personalized treatment regimen.

Язык: Английский

Процитировано

21
ATR protects ongoing and newly assembled DNA replication forks through distinct mechanisms DOI Creative Commons

Wendy Leung,

Antoine Simoneau, Sneha Saxena

и другие.

Cell Reports, Год журнала: 2023, Номер 42(7), С. 112792 - 112792

Опубликована: Июль 1, 2023

The ATR kinase safeguards genomic integrity during S phase, but how protects DNA replication forks remains incompletely understood. Here, we combine four distinct assays to analyze functions at ongoing and newly assembled upon inhibition by hydroxyurea. At forks, inhibitor (ATRi) increases MRE11- EXO1-mediated nascent degradation from PrimPol-generated, single-stranded (ssDNA) gaps. ATRi also exposes template ssDNA through fork uncoupling degradation. Electron microscopy reveals that reduces reversed increasing gap-dependent new triggers CtIP-initiated EXO1, exposing ssDNA. Upon PARP inhibition, preferentially exacerbates in BRCA1/2-deficient cells disrupts the restored gap protection BRCA1-deficient, PARP-inhibitor-resistant cells. Thus, mechanisms, providing an extended view of ATR's stabilizing forks.

Язык: Английский

Процитировано

21
Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases DOI Creative Commons
Anastasia Hale, Ashna Dhoonmoon,

Joshua Straka

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Окт. 7, 2023

Accumulation of single stranded DNA (ssDNA) gaps in the nascent strand during replication has been associated with cytotoxicity and hypersensitivity to genotoxic stress, particularly upon inactivation BRCA tumor suppressor pathway. However, how ssDNA contribute genotoxicity is not well understood. Here, we describe a multi-step nucleolytic processing stress-induced which converts them into cytotoxic double breaks (DSBs). We show that are extended bidirectionally by MRE11 3'-5' direction EXO1 5'-3' direction, process suppressed Subsequently, parental at gap cleaved endonuclease generating break. also exposure bisphenol A (BPA) diethylhexyl phthalate (DEHP), widespread environmental contaminants due their use plastics manufacturing, causes replication. These processed through same mechanism described above generate DSBs. Our work sheds light on both relevance as major determinants genomic instability, they instability cytotoxicity.

Язык: Английский

Процитировано

21
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

Процитировано

18