NAR cancer最新文献_第4页

Base excision repair within structure-forming repeat sequences and its impact on cancer and other diseases. 结构形成重复序列内的碱基切除修复及其对癌症和其他疾病的影响。

IF 4.6

NAR cancer Pub Date : 2025-12-17 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf051

Carson B Cohen, Millie C Coombes, Christopher P Merlo, Chantal A Kontor, Riaz Meah, Amy M Whitaker

{"title":"Base excision repair within structure-forming repeat sequences and its impact on cancer and other diseases.","authors":"Carson B Cohen, Millie C Coombes, Christopher P Merlo, Chantal A Kontor, Riaz Meah, Amy M Whitaker","doi":"10.1093/narcan/zcaf051","DOIUrl":"10.1093/narcan/zcaf051","url":null,"abstract":"Oxidative DNA damage is a major driver of genome instability and human disease. Among the various types of oxidative DNA base lesions, 8-oxo-7,8-dihydroguanine (8oxoG) is particularly prevalent due to guanine's low oxidation potential and the abundance of guanine-rich (G-rich) sequences across the genome. Structure-forming repeat sequences, which are commonly G-rich, can adopt alternative DNA secondary structures that further expose nucleobases to oxidative damage. The base excision repair (BER) pathway is primarily responsible for the repair of 8oxoG lesions; however, the complex topologies and dynamic conformations formed by these repeat sequences present challenges for complete repair. Inefficient BER within these structures can lead to DNA strand breaks, mutations, and large chromosomal rearrangements, all of which are associated with human disease. Notably, structure-forming repeat sequences are often enriched at regulatory genomic regions, where BER can directly influence processes such as replication and transcription. This review summarizes current insights into BER activity within oxidatively damaged structure-forming repeat sequences and highlights how repair efficiency within these sequences impacts genome stability and disease.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf051"},"PeriodicalIF":4.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12709190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

What is in a name? Rethinking SMUG1 in genome maintenance. 名字里有什么？重新思考SMUG1在基因组维持中的作用。

IF 4.6

NAR cancer Pub Date : 2025-12-12 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf050

Natalie Rudolfova, Alexander Myhr Skjetne, Nicola P Montaldo, Torkild Visnes, Hilde Loge Nilsen, Maurice Michel

{"title":"What is in a name? Rethinking SMUG1 in genome maintenance.","authors":"Natalie Rudolfova, Alexander Myhr Skjetne, Nicola P Montaldo, Torkild Visnes, Hilde Loge Nilsen, Maurice Michel","doi":"10.1093/narcan/zcaf050","DOIUrl":"10.1093/narcan/zcaf050","url":null,"abstract":"Small base lesions in DNA are primarily repaired through the base excision repair pathway, which is initiated by DNA glycosylases. This review focuses on single-strand selective monofunctional uracil-DNA glycosylase (SMUG1), an enzyme whose name incompletely captures its broader biological roles. SMUG1 excises a wide range of substrates beyond uracil, shows a preference for double-stranded DNA, and has been reported to be a bifunctional DNA glycosylase with a weak lyase activity. Moreover, SMUG1 plays roles extending beyond DNA repair, including functions in RNA quality control and RNA biogenesis. Recently, genetic interactions have been described between SMUG1 and proteins that safeguard stressed replication forks, implicating a function for SMUG1 in cancer cell biology. Understanding SMUG1's full repertoire is key to uncovering its role in genome maintenance and unlocking its potential as a therapeutic target. Here, we review the biochemical properties reported for SMUG1 and its distinct functions from other uracil-DNA glycosylases in vivo. We also highlight the emerging role of SMUG1 in cancer cells and its potential as a therapeutic target, emphasizing the need to define the genetic and molecular contexts in which its modulation may be beneficial.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf050"},"PeriodicalIF":4.6,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12699328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145758966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PARP inhibitor resistance in IDH1-mutant cancers due to loss of end protection factors, 53BP1 and REV7. 由于末端保护因子53BP1和REV7的缺失，idh1突变癌症中PARP抑制剂的耐药性。

IF 4.6

NAR cancer Pub Date : 2025-12-03 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf047

Daniel Andrés Colón-Ríos, Jonathan Dow, Adam Krysztofiak, Yanfeng Liu, Faye A Rogers, Peter M Glazer

{"title":"PARP inhibitor resistance in IDH1-mutant cancers due to loss of end protection factors, 53BP1 and REV7.","authors":"Daniel Andrés Colón-Ríos, Jonathan Dow, Adam Krysztofiak, Yanfeng Liu, Faye A Rogers, Peter M Glazer","doi":"10.1093/narcan/zcaf047","DOIUrl":"10.1093/narcan/zcaf047","url":null,"abstract":"Acquired resistance presents a major challenge for targeted therapies, with initially responsive tumors eventually reverting underlying vulnerabilities. Our group recently reported that cancers harboring isocitrate dehydrogenase 1/2 (IDH1/2) mutations have defective recruitment of homology-directed repair (HDR) factors to sites of DNA damage and consequent sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi), a vulnerability that is being tested in clinical trials. To probe potential mechanisms by which resistance to PARPi might arise in this setting, we modeled PARPi resistance in IDH-mutant tumors via serial transplantation of patient-derived xenografts in mice treated with PARPi. An analysis of candidate DNA repair factors in these resistant tumor populations identified downregulation of two end protection factors that are negative regulators of HDR, 53BP1, and REV7. Knockout of these factors by CRISPR-Cas9 in IDH1-mutant cancer cells conferred robust resistance to PARPi and restored HDR capacity. To overcome this resistance, we found that treatment with the receptor tyrosine kinase inhibitor, cediranib, previously reported to suppress expression of downstream HDR factors, resensitizes 53BP1 and REV7-knockout cells to PARPi treatment. Our findings identify key pathways driving PARPi resistance in IDH1-mutant cancers and highlight potential therapeutic strategies to overcome this resistance.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf047"},"PeriodicalIF":4.6,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12675010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145703505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A common food mutagen promotes intestinal carcinogenesis by multiple mechanisms in mouse models of Lynch syndrome. 一种常见的食物诱变剂在Lynch综合征小鼠模型中通过多种机制促进肠道癌变。

IF 4.6

NAR cancer Pub Date : 2025-12-03 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf045

Emily Rayner, Anastasia Tsaalbi-Shtylik, Lemelinda Marques, Cedrick Agaser, Hailiang Mei, Davy Cats, Sophie van Zanen-Gerhardt, Daniela Salvatori, Niels de Wind

{"title":"A common food mutagen promotes intestinal carcinogenesis by multiple mechanisms in mouse models of Lynch syndrome.","authors":"Emily Rayner, Anastasia Tsaalbi-Shtylik, Lemelinda Marques, Cedrick Agaser, Hailiang Mei, Davy Cats, Sophie van Zanen-Gerhardt, Daniela Salvatori, Niels de Wind","doi":"10.1093/narcan/zcaf045","DOIUrl":"10.1093/narcan/zcaf045","url":null,"abstract":"Lynch syndrome (LS) is a colorectal cancer predisposition caused by an inherited heterozygous defect in any of four DNA mismatch repair (MMR) genes. MMR prevents nucleotide substitution mutations by correcting errors of replication opposite undamaged or subtly altered nucleotides. Here, we investigated whether dietary mutagens, which generally induce helix-distorting nucleotide lesions, affect LS-associated carcinogenesis. To this aim, we exposed mouse models of LS to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a food-derived heterocyclic amine that selectively adducts guanines. PhIP exposure induced loss of the wild-type MMR allele in heterozygous intestinal stem cells, leading to MMR deficiency and to impaired DNA damage signalling associated with the clonal expansion of MMR-deficient intestinal stem cells. Whole-genome sequencing revealed that PhIP becomes significantly more mutagenic in intestinal stem cells when MMR is lost, inducing not only PhIP-guanine adduct-mediated C:G>A:T transversions but also a broader substitution spectrum that resembles the spontaneous mutational signature of LS-associated colorectal cancer. Thus, MMR corrects PhIP-induced misincorporations outside of adducted guanines. Chronic PhIP exposure of intestine-specific MMR-deficient mice induced adenocarcinomas with histopathological features of LS-associated CRC. This study implicates food-derived mutagens in multiple stages of LS-associated carcinogenesis, including allelic loss, and defective DNA damage signalling and compound hypermutagenesis in the resulting MMR-deficient cells.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf045"},"PeriodicalIF":4.6,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12675011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145703590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reversing uL3-mediated chemoresistance through synergistic combination of 5-FU and G-quadruplex ligands. 通过5-FU和g -四联体配体的协同联合逆转ul3介导的化学耐药。

IF 4.6

NAR cancer Pub Date : 2025-11-28 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf046

Anna Di Porzio, Annalisa Pecoraro, Camilla Danisi, Carolina Persico, Ludovica D'Auria, Marcello Germoglio, Nunzia Iaccarino, Isidoro Feliciello, Concetta Giancola, Antonio Randazzo, Giulia Russo, Annapina Russo

{"title":"Reversing uL3-mediated chemoresistance through synergistic combination of 5-FU and G-quadruplex ligands.","authors":"Anna Di Porzio, Annalisa Pecoraro, Camilla Danisi, Carolina Persico, Ludovica D'Auria, Marcello Germoglio, Nunzia Iaccarino, Isidoro Feliciello, Concetta Giancola, Antonio Randazzo, Giulia Russo, Annapina Russo","doi":"10.1093/narcan/zcaf046","DOIUrl":"10.1093/narcan/zcaf046","url":null,"abstract":"Chemoresistance represents a significant challenge in the chemotherapy of colorectal cancer (CRC), limiting the effectiveness. In this regard, gene expression heterogeneity plays a critical role, influencing cancer cell adaptability and survival under chemotherapy. Our previous data revealed that ribosomal protein uL3 positively correlates with both chemoresistance and poor prognosis in CRC patients. This study explores the combination of 5-fluorouracil (5-FU), the first-line treatment of CRC, with G-quadruplex (G4) ligands, which have recently emerged as promising candidates for cancer therapy, to overcome uL3-mediated chemoresistance. We found that resistant p53-deficient and uL3-silenced CRC cells showed increased levels of G4 structures compared to both sensitive p53-deficient and p53-proficient cells, thereby exhibiting vulnerability to the cytotoxic effects of two well-established G4 ligands, pyridostatin (PDS) and RHPS4. The combination of 5-FU with PDS or RHPS4 exhibited a synergistic effect, selectively targeting tumor cells. This approach enabled a >10-fold reduction in the 5-FU dose, improving treatment efficacy. The effectiveness of this combination was further validated in vivo using uL3-silenced CRC cell-derived xenografts in a chicken embryo model. Overall, our findings highlight a novel and promising combination strategy that targets chemoresistance in CRCs characterized by non-functional p53 and reduced levels of uL3.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf046"},"PeriodicalIF":4.6,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12661320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145650666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transcriptional pause release at enhancers mediates cell identity. 增强子的转录暂停释放介导细胞身份。

IF 4.6

NAR cancer Pub Date : 2025-11-11 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf039

Thomas L Ekstrom, Steven A Johnsen

{"title":"Transcriptional pause release at enhancers mediates cell identity.","authors":"Thomas L Ekstrom, Steven A Johnsen","doi":"10.1093/narcan/zcaf039","DOIUrl":"10.1093/narcan/zcaf039","url":null,"abstract":"This short review highlights recent findings related to transcription factor-mediated RNA polymerase II (Pol II) pause release at enhancers and its role in regulating cell identity. We discuss how the transcriptional state of Pol II, either paused or released, shapes enhancer-promoter interactions, thereby influencing gene expression programs that define cell identity. We further summarize current knowledge of DNA-binding transcription factors that regulate Pol II pause release at enhancers and explore how this process influences cell identity. We propose a novel concept of therapy-induced molecular amnesia, where temporary inhibition of enhancer-proximal Pol II pause release and enhancer RNA transcription affects enhancer-promoter interactions differently in distinct cellular contexts. In some contexts, preservation of enhancer-promoter interactions allows rapid transcriptional reactivation and maintenance of cell identity upon recovery. In other contexts, repeated inhibition of enhancer RNA transcription leads to the permanent dissociation of enhancer-promoter interactions and loss of cell identity. Our model suggests that manipulating Pol II pause release at enhancers could selectively reverse certain aggressive tumor cell identities, limit tumor cell plasticity, and improve therapy responsiveness.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf039"},"PeriodicalIF":4.6,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12604671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145508636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DVFGCDR: a dual-view fusion graph neural network for cancer drug response prediction. DVFGCDR：用于肿瘤药物反应预测的双视图融合图神经网络。

IF 4.6

NAR cancer Pub Date : 2025-11-07 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf043

Weihong Huang, Shengwei Qin, Haohao Li, Hancan Zhu, Yuhua Yao, Zhong Li

引用次数: 0

Polymerase θ-what does it see, and why does it matter for cancer therapy? 聚合酶θ-它能看到什么，为什么它对癌症治疗很重要？

IF 4.6

NAR cancer Pub Date : 2025-11-06 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf042

Dale A Ramsden, Gaorav P Gupta

引用次数: 0

Targeting DNA repair mechanisms in cancer therapy: the role of small molecule DNA repair inhibitors. 靶向DNA修复机制在癌症治疗中的作用：小分子DNA修复抑制剂的作用。

IF 4.6

NAR cancer Pub Date : 2025-11-03 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf040

Seula Jeong, Yuheon Chung, Soomin Heo, Kyungjae Myung

{"title":"Targeting DNA repair mechanisms in cancer therapy: the role of small molecule DNA repair inhibitors.","authors":"Seula Jeong, Yuheon Chung, Soomin Heo, Kyungjae Myung","doi":"10.1093/narcan/zcaf040","DOIUrl":"10.1093/narcan/zcaf040","url":null,"abstract":"Genomic instability and the accumulation of DNA damage are hallmarks of cancer, often resulting from defects in DNA repair pathways. While normal cells rely on highly coordinated DNA damage response (DDR) mechanisms to maintain genomic integrity, cancer cells exploit aberrant DDR regulation to sustain uncontrolled proliferation and survival. Despite significant advancements in chemotherapy, targeted therapy, and immunotherapy, the emergence of resistance remains a major challenge in cancer treatment. Small molecule inhibitors targeting key DDR proteins have emerged as promising therapeutic agents, not only as direct anticancer drugs but also as indispensable tools for dissecting the molecular intricacies of DNA repair. Recent therapeutic approaches leverage synthetic lethality and DDR pathway vulnerabilities to selectively eradicate tumor cells while minimizing damage to normal tissues. These inhibitors provide insights into mechanisms of tumor resistance, facilitating the rational design of combination therapies to enhance treatment efficacy. This review examines the latest advancements in DNA repair-targeted therapeutics, with a focus on small molecule inhibitors currently under clinical investigation. Additionally, we discuss emerging strategies for optimizing DDR-targeted interventions, including biomarker-driven patient selection and rational drug combinations. Understanding these molecular interactions will contribute to the development of novel, more effective treatment paradigms for cancer therapy.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf040"},"PeriodicalIF":4.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12582025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Shining light on drug discovery: optogenetic screening for TopBP1 biomolecular condensate inhibitors. 照亮药物发现：TopBP1生物分子凝聚抑制剂的光遗传学筛选。

IF 4.6

NAR cancer Pub Date : 2025-11-03 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf041

Laura Morano, Nadia Vie, Adam Aissanou, Dana Hodroj, Véronique Garambois, Alexandra Fauvre, Alexy Promonet, Tom Egger, Benoît Bordignon, Cédric Hassen-Khodja, Solène Fiachetti, Jihane Basbous, Céline Gongora, Angelos Constantinou

{"title":"Shining light on drug discovery: optogenetic screening for TopBP1 biomolecular condensate inhibitors.","authors":"Laura Morano, Nadia Vie, Adam Aissanou, Dana Hodroj, Véronique Garambois, Alexandra Fauvre, Alexy Promonet, Tom Egger, Benoît Bordignon, Cédric Hassen-Khodja, Solène Fiachetti, Jihane Basbous, Céline Gongora, Angelos Constantinou","doi":"10.1093/narcan/zcaf041","DOIUrl":"10.1093/narcan/zcaf041","url":null,"abstract":"Human topoisomerase IIβ binding protein 1 (TopBP1) is a scaffold protein involved in DNA replication initiation, DNA repair, transcription regulation, and checkpoint activation. TopBP1 forms nuclear condensates that act as a molecular switch to amplify ATR activity and promote the activation of the checkpoint effector kinase Chk1. In cancer cells, ATR activity is crucial to tolerate the intrinsically high level of DNA lesions and obstacles that block replication fork progression. Thus, ATR inhibitors are currently tested in clinical trials, often in combination with chemotherapy drugs. However, resistance and toxicity are still major issues. The weak interactions that hold TopBP1 condensates together are highly sensitive to changes in the cellular milieu, suggesting that small molecules may alter the formation of TopBP1 condensates. Here, we developed a high-throughput screening system to identify TopBP1 condensation modulators. This system allowed us to identify FDA-approved drugs, including thimerosal and quinacrine, that inhibit TopBP1 condensation and block the activation of ATR/Chk1 signaling. Mechanistically, quinacrine impaired TopBP1's ability to associate with chromatin, thereby interfering with its capacity to form condensates. Furthermore, quinacrine enhanced the therapeutic efficacy of 5-fluorouracil and irinotecan, components of the clinically used FOLFIRI regimen in a mouse model of peritoneal carcinomatosis from colorectal cancer.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf041"},"PeriodicalIF":4.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12582362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0