Cell cycle regulation of polymerase theta mediated end-joining underlies its sensitivity to loss of BLM-DNA2 DOI Creative Commons
Connor P. McBrine, Ryan B. Jensen, Megan C. King

и другие.

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

Опубликована: Окт. 4, 2024

Abstract DNA double-strand breaks (DSBs) are predominantly resolved by the error-prone non-homologous end-joining (NHEJ) or high-fidelity homologous recombination (HR) repair pathways. NHEJ involves minimal end-processing and drives direct ligation of broken ends, while HR first requires a DSB resection step that degrades 5’ strands to generate 3’ ssDNA tails necessary for homology search. When fails, an alternative pathway involving polymerase theta can serve as backup mechanism annealing ligating microhomologies present in on either side resected DSB. Resection is early commits HR, therefore considered prerequisite TMEJ well. It has been proposed exonuclease EXO1 helicase/nuclease complex BLM-DNA2 have redundant roles resection, may both contribute TMEJ. Here, we use sensitive deep-sequencing approach identify outcomes at endogenous locus response genetic chemical perturbation machinery. While observe our findings highlight predominant role facilitating However, careful cell cycle analysis revealed BLM-DNA primarily contributes ensuring normal progression G2/M transition, required become activated. We propose rather than direct, mechanistic critical functions BLM DNA2 genome replication largely account their contribution efficient

Язык: Английский

Mechanism of BRCA1–BARD1 function in DNA end resection and DNA protection DOI Creative Commons
Ilaria Ceppi, Maria Rosaria Dello Stritto,

Martin Mütze

и другие.

Nature, Год журнала: 2024, Номер 634(8033), С. 492 - 500

Опубликована: Сен. 11, 2024

Язык: Английский

Процитировано

11
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
EXO1 and DNA2-mediated ssDNA gap expansion is essential for ATR activation and to maintain viability in BRCA1-deficient cells DOI Creative Commons
Néstor García‐Rodríguez,

Iria Domínguez-García,

María del Carmen Domínguez-Pérez

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер 52(11), С. 6376 - 6391

Опубликована: Май 9, 2024

DNA replication faces challenges from lesions originated endogenous or exogenous sources of stress, leading to the accumulation single-stranded (ssDNA) that triggers activation ATR checkpoint response. To complete genome in presence damaged DNA, cells employ damage tolerance mechanisms operate not only at stalled forks but also ssDNA gaps by repriming synthesis downstream lesions. Here, we demonstrate human accumulate post-replicative following replicative stress induction. These gaps, initiated PrimPol and expanded long-range resection factors EXO1 DNA2, constitute principal origin signal responsible for upon contrast forks. Strikingly, loss DNA2 results synthetic lethality when combined with BRCA1 deficiency, BRCA2. This phenomenon aligns observation alone contributes expansion gaps. Remarkably, BRCA1-deficient become addicted overexpression EXO1, BLM. dependence on unveils a new vulnerability BRCA1-mutant tumors, shedding light potential therapeutic targets these cancers.

Язык: Английский

Процитировано

8
BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis DOI Creative Commons
Daniel Salas‐Lloret, Néstor García‐Rodríguez, Emily Soto-Hidalgo

и другие.

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

Опубликована: Май 20, 2024

Abstract Deficiencies in the BRCA1 tumor suppressor gene are main cause of hereditary breast and ovarian cancer. is involved Homologous Recombination DNA repair pathway and, together with BARD1, forms a heterodimer ubiquitin E3 activity. The relevance BRCA1/BARD1 activity for suppression remains controversial. Here, we observe that not required or resistance to Olaparib. Using TULIP2 methodology, which enables direct identification E3-specific ubiquitination substrates, identify substrates BRCA1/BARD1. We find PCNA ubiquitinated by unperturbed conditions independently RAD18. avoids formation ssDNA gaps during replication promotes continuous synthesis. These results provide additional insight about importance Recombination.

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
Targeting FEN1/EXO1 to enhance efficacy of PARP inhibition in triple-negative breast cancer DOI

Mallory I. Frederick,

Elicia Fyle,

Anna Clouvel

и другие.

Translational Oncology, Год журнала: 2025, Номер 54, С. 102337 - 102337

Опубликована: Март 6, 2025

Язык: Английский

Процитировано

0
EXO1's pan-cancer roles: diagnostic, prognostic, and immunological analyses through bioinformatics DOI Creative Commons
Zheng Liu,

Shu Huang,

Rui Luo

и другие.

Discover Oncology, Год журнала: 2025, Номер 16(1)

Опубликована: Март 12, 2025

Cancer remains a leading cause of mortality worldwide, with human exonuclease 1 (EXO1) emerging as key player in DNA repair and damage response pathways, critical for genomic stability tumor evolution. The aim this study was to conduct comprehensive pan-cancer analysis elucidate the multifaceted roles EXO1 various malignancies. Leveraging public databases including TCGA, GTEx, HPA, cBioPortal, UALCAN, STRING, CancerSEA TISIDB database, we examined EXO1's expression, diagnostic potential, prognostic significance, mutational characteristics, functional roles, immunological effects across different cancer types. found be upregulated multiple cancers, significant potential indicated by high AUC values ROC analyses. Elevated expression correlated adverse prognosis several types, breast, lung, pancreatic cancers. Epigenetic alterations, methylation mRNA modifications, were also associated expression. Enrichment analyses identified EXO1-related genes involved recombination, replication, repair, GSEA implicating cell cycle regulation processing pathways. Importantly, immunogenomic revealed role modulating microenvironment, it is immune infiltration cytokine suggesting its involvement immunology regulation. These results implied that biomarker malignancies, therapeutic target immunomodulatory processes within microenvironment.

Язык: Английский

Процитировано

0
Overview of Roles of Novel Components in the Regulation of DNA Damage Repair in BRCA1-Deficient Cancers: An Update DOI Creative Commons
N. V. Nguyen, Dominic Arris, Manh Tien Tran

и другие.

DNA, Год журнала: 2025, Номер 5(2), С. 17 - 17

Опубликована: Апрель 1, 2025

Cancers that arise from germline mutations of breast cancer associated gene 1 (BRCA1), which is a crucial player in homologous recombination (HR) DNA repair, are vulnerable to DNA-damaging agents such as platinum and PARP inhibitors (PARPis). Increasing evidence suggests BRCA1 an essential driver all phases the cell cycle, thereby maintaining orderly steps during cycle progression. Specifically, loss activity causes S-phase, G2/M, spindle checkpoints, centrosome duplication be dysregulated, blocking proliferation inducing apoptosis. In vertebrates, HR genes and/or BRCA2 lethal, since prerequisite for genome integrity. Thus, cells utilize alternative repair pathways non-homologous end joining (NHEJ) cope with function. this review, we attempt update discuss how these novel components regulating damage (DDR) BRCA1-deficient cancers.

Язык: Английский

Процитировано

0
Positioning Loss of PARP1 Activity as the Central Toxic Event in BRCA-Deficient Cancer DOI Creative Commons
Nathan J. MacGilvary, Sharon B. Cantor

DNA repair, Год журнала: 2024, Номер 144, С. 103775 - 103775

Опубликована: Окт. 19, 2024

The mechanisms by which poly(ADP-ribose) polymerase 1 (PARP1) inhibitors (PARPi)s inflict replication stress and/or DNA damage are potentially numerous. PARPi toxicity could derive from loss of its catalytic activity physical trapping PARP1 onto that perturbs not only function in repair and replication, but also obstructs compensating pathways. combined disruption with either the hereditary breast ovarian cancer genes, BRCA1 or BRCA2 (BRCA), results synthetic lethality. This has driven development PARP as therapies for BRCA-mutant cancers. In this review, we focus on recent findings highlight activity, rather than PARPi-induced allosteric trapping, central to efficacy BRCA deficient cells. However, review PARP-trapping is an effective strategy other genetic deficiencies. Together, conclude mechanism-of-action unilateral; enhanced differentially killing depending context. Therefore, effectively targeting cells requires intricate understanding their key underlying vulnerabilities.

Язык: Английский

Процитировано

4
Mechanisms and regulation of DNA end resection in the maintenance of genome stability DOI
Raphaël Ceccaldi, Petr Ćejka

Nature Reviews Molecular Cell Biology, Год журнала: 2025, Номер unknown

Опубликована: Март 25, 2025

Язык: Английский

Процитировано

0