HMCES corrupts replication fork stability during base excision repair in homologous recombination deficient cells DOI Creative Commons
María José Peña-Gómez,

Yaiza Rodríguez-Martín,

Marta del Rio Oliva

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 31, 2024

Abstract Apurinic/apyrimidinic (AP) sites and single-strand breaks (SSB) arising from base excision repair (BER) during misincorporation of damaged nucleobases may hinder replication fork stability in homologous recombination-deficient (HRD) cells. At templated AP-sites, HMCES DNA-protein crosslinks (DPC) regulate speed while avoiding APE1-mediated cytotoxic double-strand (DSB). Whereas the role at template DNA strand is well studied, its consequences on nascent are less understood. Here, we provide evidence that play detrimental roles removal 5- hydroxymethyl-2’-deoxycytidine (5hmdC)-derived 5-hydroxymethyl-2’-deoxyuridine (5hmdU) by BER forks. HRD cells display heightened chromatin levels, which increase upon 5hmdC exposure, suggesting binds both spontaneous 5hmdC-induced AP-sites. depletion largely suppresses 5hmdC- mediated Fancd2 -/- defects, chromosomal aberrations cell lethality, responsible for impairment lethality observed Therefore, HMCES-DPCs a novel source BER-initiated PRIMPOL-mediated ssDNA gaps, implying endogenous DPCs as damage tumours. Teaser Covalent binding to blocks progression kills recombination deficient cancer

Язык: Английский

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
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
RAD51 protects abasic sites to prevent replication fork breakage DOI Creative Commons
Yodhara Wijesekara Hanthi, Miguel Angel Ramírez-Otero, Robert Appleby

и другие.

Molecular Cell, Год журнала: 2024, Номер 84(16), С. 3026 - 3043.e11

Опубликована: Авг. 1, 2024

Abasic sites are DNA lesions repaired by base excision repair. Cleavage of unrepaired abasic in single-stranded (ssDNA) can lead to chromosomal breakage during replication. How rupture is prevented remains poorly understood. Here, using cryoelectron microscopy (cryo-EM), Xenopus laevis egg extracts, and human cells, we show that RAD51 nucleofilaments specifically recognize protect sites, which increase association rate DNA. In the absence BRCA2 or RAD51, accumulate as a result methylation, oxidation, deamination, inducing ssDNA gaps make replicating fibers sensitive APE1. assembled on prevents site cleavage MRE11-RAD50 complex, suppressing replication fork triggered an excess POLθ polymerase inhibition. Our study highlights critical role safeguarding against templates stemming from alterations, ensuring genomic stability.

Язык: Английский

Процитировано

10
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
Structural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2 DOI Creative Commons
Robert Appleby, Luay Joudeh,

Katie Cobbett

и другие.

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

Опубликована: Ноя. 2, 2023

Abstract The BRCA2 tumour suppressor protein preserves genomic integrity via interactions with the DNA-strand exchange RAD51 in homology-directed repair. RAD51-binding TR2 motif at C-terminus is essential for protection and restart of stalled replication forks. Biochemical evidence shows that recognises filamentous RAD51, but existing models binding to lack a structural basis. Here we used cryo-electron microscopy structure-guided mutagenesis elucidate mechanism nucleoprotein filaments human RAD51. We find binds across protomer interface filament, acting as brace adjacent molecules. targets an acidic-patch on serves recruitment hub fission yeast Rad51 recombination mediators Rad52 Rad55-Rad57. Our findings provide rationale filament stabilisation by reveal common filament.

Язык: Английский

Процитировано

16
Role of Translesion DNA Synthesis in the Metabolism of Replication-associated Nascent Strand Gaps DOI Creative Commons

Jude B. Khatib,

Claudia M. Nicolae, George‐Lucian Moldovan

и другие.

Journal of Molecular Biology, Год журнала: 2023, Номер 436(1), С. 168275 - 168275

Опубликована: Сен. 14, 2023

Язык: Английский

Процитировано

15
Positive and negative regulators of RAD51/DMC1 in homologous recombination and DNA replication DOI
Masaru Ito, Yurika Fujita, Akira Shinohara

и другие.

DNA repair, Год журнала: 2023, Номер 134, С. 103613 - 103613

Опубликована: Дек. 13, 2023

Язык: Английский

Процитировано

14
BRCA1 and 53BP1 regulate reprogramming efficiency by mediating DNA repair pathway choice at replication-associated double-strand breaks DOI Creative Commons
Daniela Georgieva, Ning Wang, Angelo Taglialatela

и другие.

Cell Reports, Год журнала: 2024, Номер 43(4), С. 114006 - 114006

Опубликована: Март 30, 2024

Reprogramming to pluripotency is associated with DNA damage and requires the functions of BRCA1 tumor suppressor. Here, we leverage separation-of-function mutations in BRCA1/2 as well physical and/or genetic interactions between its repair proteins ascertain relevance homology-directed (HDR), stalled fork protection (SFP), replication gap suppression (RGS) somatic cell reprogramming. Surprisingly, loss SFP RGS inconsequential for transition pluripotency. In contrast, cells deficient HDR, but proficient RGS, reprogram reduced efficiency. Conversely, restoration HDR function through inactivation 53bp1 rescues reprogramming Brca1-deficient cells, leads elevated enhanced mouse human cells. These results demonstrate that especially dependent on replication-associated double-strand breaks (DSBs) by activity BRCA2 can be improved absence 53BP1.

Язык: Английский

Процитировано

5
(Single-stranded DNA) gaps in understanding BRCAness DOI Creative Commons
Anne Schreuder,

Tiemen J. Wendel,

Carlo G.V. Dorresteijn

и другие.

Trends in Genetics, Год журнала: 2024, Номер 40(9), С. 757 - 771

Опубликована: Май 23, 2024

The tumour-suppressive roles of BRCA1 and 2 have been attributed to three seemingly distinct functions - homologous recombination, replication fork protection, single-stranded (ss)DNA gap suppression their relative importance is under debate. In this review, we examine the origin resolution ssDNA gaps discuss recent advances in understanding role BRCA1/2 suppression. There are ample data showing that accumulation BRCA1/2-deficient cells linked genomic instability chemosensitivity. However, it remains unclear whether there a causative function cannot unambiguously be dissected from other functions. We therefore conclude closely intertwined not mutually exclusive.

Язык: Английский

Процитировано

5
‘Where is my gap’: mechanisms underpinning PARP inhibitor sensitivity in cancer DOI Creative Commons

Lauryn Buckley-Benbow,

Alessandro Agnarelli, Roberto Bellelli

и другие.

Biochemical Society Transactions, Год журнала: 2025, Номер 53(01)

Опубликована: Фев. 10, 2025

The introduction of poly-ADP ribose polymerase (PARP) inhibitors (PARPi) has completely changed the treatment landscape breast cancer susceptibility 1–2 (BRCA1–BRCA2)-mutant cancers and generated a new avenue research in fields DNA damage response therapy. Despite this, primary secondary resistances to PARPi have become challenge clinic, novel therapies are urgently needed address this problem. After two decades research, unifying model explaining sensitivity cells is still missing. Here, we review current knowledge field increasing evidence pointing crucial role for replicative gaps mediating sensitization BRCA-mutant ‘wild-type’ cells. Finally, discuss challenges be addressed further improve utilization tackle emergence resistance clinical context.

Язык: Английский

Процитировано

0