EXO1 protects BRCA1-deficient cells against toxic DNA lesions

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(4), P. 659 - 674.e7

Published: Jan. 23, 2024

Inactivating mutations in the BRCA1 and BRCA2 genes impair DNA double-strand break (DSB) repair by homologous recombination (HR), leading to chromosomal instability cancer. Importantly, BRCA1/2 deficiency also causes therapeutically targetable vulnerabilities. Here, we identify dependency on end resection factor EXO1 as a key vulnerability of BRCA1-deficient cells. generates poly(ADP-ribose)-decorated lesions during S phase that associate with unresolved DSBs genomic but not wild-type or BRCA2-deficient Our data indicate BRCA1/EXO1 double-deficient cells accumulate due impaired single-strand annealing (SSA) top their HR defect. In contrast, retain SSA activity absence hence tolerate loss. Consistent EXO1-mediated SSA, find BRCA1-mutated tumors show elevated expression increased SSA-associated scars compared BRCA1-proficient tumors. Overall, our findings uncover promising therapeutic target for

Language: Английский

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Colorectal cancer microbiome programs DNA methylation of host cells by affecting methyl donor metabolism

Genome Medicine, Journal Year: 2024, Volume and Issue: 16(1)

Published: June 5, 2024

Colorectal cancer (CRC) arises from complex interactions between host and environment, which include the gut tissue microbiome. It is hypothesized that epigenetic regulation by microbiota a fundamental interface commensal microbes dynamically influence intestinal biology. The aim of this study to explore interplay DNA methylation in CRC.

Language: Английский

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EXO1 is a key gene for lung-resident memory T cells and has diagnostic and predictive values for lung adenocarcinoma

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 1, 2025

Lung adenocarcinoma (LUAD) is a very common and lethal kind of lung malignancy. An increasing number studies indicated that tissue-resident memory T (TRM) cells played significant roles in anti-cancer immunity. In our previous study, EXO1 was found to be core gene for TRM the prognosis LUAD. However, tumor microenvironment, its application diagnosis prediction LUAD are still inadequately explored. this RNA expression, DNA methylation, CNV, somatic mutation data EXO1, corresponding patients' clinical information from publicly available databases were analyzed using bioinformatic methods. The results validated through immunohistochemical staining samples. showed aberrantly highly expressed tissues. High expression risky factor patients. level associated with many features such as TNM stages. It can also distinguish normal tissues accurately. correlated infiltration immune cells, high an adverse effect on patients receiving anti-PD-1/PD-L1 immunotherapy. Moreover, had worse DSS, DFI PFI.

Language: Английский

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A large-scale genome-wide association study on female genital tract polyps highlights role of DNA repair, cell proliferation, and cell growth

Human Reproduction, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Abstract STUDY QUESTION Can a large-scale genome-wide association study (GWAS) meta-analysis identify genomic risk loci and likely involved genes for female genital tract (FGT) polyps, provide insights into the biological mechanism underlying their development, inform of potential overlap with other traits, including endometrial cancer? SUMMARY ANSWER GWAS FGT polyps highlights potentially shared mechanisms between polyp development cancerous processes. WHAT IS KNOWN ALREADY Small-scale candidate gene studies have focused on processes such as oestrogen stimulation inflammation to clarify biology behind polyps. However, exact is still elusive. At same time, approach, which has become gold standard in complex disease genetics, never been used uncover genetics DESIGN, SIZE, DURATION We performed total 36 984 women (International Classification Diseases (ICD-10) diagnosis code N84) 420 993 controls (without N84 code) European ancestry from FinnGen (11 092 cases 94 394 controls), Estonian Biobank (EstBB, 14 008 112 799 Pan-UKBB 884 213 800 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS functional annotation signals were genetic prioritize associated loci. To explore associations we look-up variants across multiple traits health conditions, correlation analysis, phenome-wide (PheWAS) ICD-10 codes. MAIN RESULTS AND THE ROLE OF CHANCE Our revealed 16 significant (P < 5 × 10−8) Based exonic signals, prioritized EEFSEC, ODF3, PRIM1, PLCE1, LRRC34/MYNN, EXO1, CHEK2 are DNA repair, cell proliferation, growth. Several identified previously linked cancer and/or uterine fibroids, highlighting tissue overgrowth Genetic analysis positive body mass index reproductive that can be classified symptoms or factors (EPs), whereas negative was observed both menopause (genetic estimate (rg) = −0.29, SE 0.08, P 8.8×10−4) sex hormone-binding globulin (SHBG) (rg −0.22, 0.04, 2.4×10−8). On phenotypic level, strongest endometriosis, excessive, frequent, irregular menstruation. LARGE SCALE DATA The complete summary statistics will made available after publication through Catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION In this study, broadly did not differentiate subtypes. Considering prevalence subtypes, assumed most included had EPs. Further research expression profile could complement substantiate importance variants. WIDER IMPLICATIONS FINDINGS findings significantly enhance our understanding involved, paving way future follow-up, turn improve diagnosis, assessment, targeted treatment options, since surgery only line diagnosed FUNDING/COMPETING INTEREST(S) This funded by Union Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED. Computations High-Performance Computing Center University Tartu. also supported Research Council (grant no. PRG1076 MOBJD1056) Horizon 2020 innovation grant (ERIN, EU952516). All authors declared no conflict interest.

Language: Английский

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EXO1 and DNA2-mediated ssDNA gap expansion is essential for ATR activation and to maintain viability in BRCA1-deficient cells

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(11), P. 6376 - 6391

Published: May 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.

Language: Английский

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SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(11)

Published: May 31, 2022

Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP are selectively active cells with homologous recombination DNA repair deficiency caused by mutations BRCA1/2 other pathway genes. Cancers proficiency respond poorly to inhibitors. that initially eventually develop drug resistance. We identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 ARN3261, which decreased double-strand break (DSB) functions produced synthetic lethality multiple both cancer cells. SIK2 is required for centrosome splitting PI3K activation regulates cell proliferation, metastasis, sensitivity chemotherapy. Here, we showed sensitized triple-negative (TNBC) xenografts enzyme activity phosphorylation class-IIa histone deacetylases (HDAC4/5/7). Furthermore, abolished HDAC4/5/7-associated transcriptional myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding regulatory regions high chromatin accessibility FANCD2, EXO1, XRCC4 genes, resulting repression their DSB pathway. The combination provides a therapeutic strategy enhance inhibitor TNBC.

Language: Английский

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A CRISPR-Cas9 screen identifies EXO1 as a formaldehyde resistance gene

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 24, 2023

Abstract Fanconi Anemia (FA) is a rare, genome instability-associated disease characterized by deficiency in repairing DNA crosslinks, which are known to perturb several cellular processes, including transcription, replication, and repair. Formaldehyde, by-product of metabolism, thought drive FA generating interstrand crosslinks (ICLs) DNA-protein (DPCs). However, the impact formaldehyde on global pathways has not been investigated thoroughly. Herein, using pangenomic CRISPR-Cas9 screen, we identify EXO1 as critical regulator formaldehyde-induced lesions. We show that knockout cell lines exhibit sensitivity leading accumulation replicative stress, double-strand breaks, quadriradial chromosomes, typical feature FA. After exposure, recruited chromatin, protects replication forks from degradation, functions parallel with pathway promote survival. In vitro, EXO1-mediated exonuclease activity proficient removing DPCs. Collectively, limits stress damage counteract instability.

Language: Английский

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EXO1: A tightly regulated nuclease

DNA repair, Journal Year: 2020, Volume and Issue: 93, P. 102929 - 102929

Published: Sept. 1, 2020

Language: Английский

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Archaeal DNA Repair Mechanisms

Biomolecules, Journal Year: 2020, Volume and Issue: 10(11), P. 1472 - 1472

Published: Oct. 23, 2020

Archaea often thrive in environmental extremes, enduring levels of heat, pressure, salinity, pH, and radiation that prove intolerable to most life. Many extremes raise the propensity for DNA damaging events thus, impact stability, placing greater reliance on molecular mechanisms recognize damage initiate accurate repair. can presumably prosper harsh DNA-damaging environments part due robust repair pathways but surprisingly, no unique have been described. Here, we review recent advances our understanding archaeal We summarize types their consequences, recognition by host enzymes, how collective activities many maintain genomic integrity.

Language: Английский

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EXO1's pan-cancer roles: diagnostic, prognostic, and immunological analyses through bioinformatics

Discover Oncology, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 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.

Language: Английский

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