NAR cancer最新文献_第2页

Sensitive detection of somatic mutations in GC-rich cancer gene promoters. 富gc癌基因启动子体细胞突变的灵敏检测。

IF 4.6

NAR cancer Pub Date : 2026-05-04 eCollection Date: 2026-06-01 DOI: 10.1093/narcan/zcag011

Meifang Qi, Preshita Sanjay Dave, Nicole Francis, Matthew DeFelice, Sam Pollock, Holly Corbitt, Irene Rin Mitsiades, Gengchao Wang, Paul Frere, Alan Fox, Gregory Khitrov, Caroline Petersen, Katie Larkin, Susanna Hamilton, Leif W Ellisen, Doga C Gulhan, Alfredo Hidalgo-Miranda, Niall Lennon, Carrie Cibulskis, Esther Rheinbay

{"title":"Sensitive detection of somatic mutations in GC-rich cancer gene promoters.","authors":"Meifang Qi, Preshita Sanjay Dave, Nicole Francis, Matthew DeFelice, Sam Pollock, Holly Corbitt, Irene Rin Mitsiades, Gengchao Wang, Paul Frere, Alan Fox, Gregory Khitrov, Caroline Petersen, Katie Larkin, Susanna Hamilton, Leif W Ellisen, Doga C Gulhan, Alfredo Hidalgo-Miranda, Niall Lennon, Carrie Cibulskis, Esther Rheinbay","doi":"10.1093/narcan/zcag011","DOIUrl":"10.1093/narcan/zcag011","url":null,"abstract":"Somatic mutations in protein-coding genes and noncoding regulatory regions are the major drivers of cancer. Only a relatively small number of somatic noncoding mutations that are likely drivers have been described to date, including those in the promoters of the TERT, FOXA1, and TP53 genes. The impact of these alterations can be profound by initiating, increasing, or abolishing gene expression. Promoter mutations in particular have been difficult to identify even from whole tumor genomes due to their high content of G and C nucleotides, which leads to loss of sequencing coverage in these regions. Therefore, the landscape of somatic drivers in gene promoters remains incomplete. Here, we present a hybrid capture assay optimized for >3000 promoters of cancer genes. We show that this assay allows for deep sequencing of challenging GC-rich promoter regions, enabling discovery of reliable point mutations, short insertions and deletions, copy number variants, and mutational signatures in cell line models as well as formalin-fixed, paraffin-embedded archival tissue samples. Our assay nominated candidate noncoding driver mutations in CDK4, SMAD3, and GATA3 in breast cancer for future functional follow-up.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 2","pages":"zcag011"},"PeriodicalIF":4.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848296","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

Efficient gene disruption with CRISPR-Cas3 in human T cells. CRISPR-Cas3在人T细胞中的高效基因破坏

IF 4.6

NAR cancer Pub Date : 2026-04-21 eCollection Date: 2026-06-01 DOI: 10.1093/narcan/zcag009

Tomoaki Fujii, Yukimi Sakoda, Kazuto Yoshimi, Kohei Takeshita, Shoji Watanabe, Ryuya Iida, Tsubasa Obo, Kazumasa Yokoyama, Koji Tamada, Tomoji Mashimo

{"title":"Efficient gene disruption with CRISPR-Cas3 in human T cells.","authors":"Tomoaki Fujii, Yukimi Sakoda, Kazuto Yoshimi, Kohei Takeshita, Shoji Watanabe, Ryuya Iida, Tsubasa Obo, Kazumasa Yokoyama, Koji Tamada, Tomoji Mashimo","doi":"10.1093/narcan/zcag009","DOIUrl":"10.1093/narcan/zcag009","url":null,"abstract":"The CRISPR-Cas9 system has been widely adopted as a genome editing tool due to its high efficiency and versatility, contributing to the development of various therapeutic strategies. However, its clinical application remains limited by safety concerns, including off-target effects and large-scale chromosomal rearrangements such as translocations and inversions. Recently, the CRISPR-Cas3 system, a Class 1 CRISPR effector complex with unidirectional DNA degradation activity, has gained attention as a potential alternative, offering reduced off-target activity. In this study, we applied the CRISPR-Cas3 system to human T cells and successfully disrupted two clinically relevant genes, T cell receptor alpha constant (TRAC) and beta-2 microglobulin (B2M). These gene deletions were associated with a reduction in both graft-versus-host disease risk and host immune rejection. Importantly, no off-target mutations were detected in CRISPR-Cas3-edited cells, in contrast to the off-target effects observed with CRISPR-Cas9. Furthermore, CAR-T cells generated by deleting TRAC or B2M using CRISPR-Cas3 maintained their antigen-specific cytotoxicity against tumor cells, while exhibiting reduced alloreactivity. These results suggest that CRISPR-Cas3 provides a safer and promising platform for genome editing in T cell engineering, with potential applications in the development of next-generation allogeneic T cell therapies.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 2","pages":"zcag009"},"PeriodicalIF":4.6,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13137050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848257","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

Uncovering novel germline variants associated with testicular germ cell tumors by exome sequencing. 通过外显子组测序揭示与睾丸生殖细胞肿瘤相关的新型生殖系变异。

IF 4.6

NAR cancer Pub Date : 2026-04-20 eCollection Date: 2026-06-01 DOI: 10.1093/narcan/zcag007

Berenice Cuevas-Estrada, Juan A Ríos-Rodríguez, José A García-Pacheco, Talia Wegman-Ostrosky, Alejandra Cervera, Nicolas Alcaraz, Michel Montalvo-Casimiro, Alejandra Barrón-Hernández, Clementina Castro-Hernández, Miguel A Jiménez-Ríos, Nora Sobrevilla-Moreno, Cristian Arriaga-Canon, Luis A Herrera, Rodrigo González-Barrios

{"title":"Uncovering novel germline variants associated with testicular germ cell tumors by exome sequencing.","authors":"Berenice Cuevas-Estrada, Juan A Ríos-Rodríguez, José A García-Pacheco, Talia Wegman-Ostrosky, Alejandra Cervera, Nicolas Alcaraz, Michel Montalvo-Casimiro, Alejandra Barrón-Hernández, Clementina Castro-Hernández, Miguel A Jiménez-Ríos, Nora Sobrevilla-Moreno, Cristian Arriaga-Canon, Luis A Herrera, Rodrigo González-Barrios","doi":"10.1093/narcan/zcag007","DOIUrl":"10.1093/narcan/zcag007","url":null,"abstract":"Testicular germ cell tumors (TGCT) are highly heritable malignancies that display increasing incidence worldwide, with rising mortality rates particularly evident among Hispanic men. However, genomic studies of TGCT have largely focused on European cohorts, limiting accurate risk prediction in other populations. We investigated rare germline variants contributing to TGCT susceptibility in a Hispanic cohort. Exome sequencing data (mean depth 60x) from 40 Mexican TGCT patients were analyzed against two ancestry-matched control groups using gene-based aggregation analyses and single-variant association. Top candidate variants were validated and replicated in an independent cohort of 211 TGCT patients, with Mexican individuals from the PAGE study serving as a third control group. Gene-based testing revealed seven genes, including MAP3K5, VAV2, and CAPN8, with nominal associations. Three previously unreported variants: rs2273499 in ARFGAP1 (OR 3.72), rs147153778 in SLCO4A1 (OR 2.21), and rs79783591 in MC4R (OR 2.31), showed statistically significant results and consistent directionality in the replication cohort, representing suggestive TGCT risk variants that warrant further validation, although none reached exome-wide significance. All three also displayed preliminary associations with mortality, indicating potential prognostic relevance. These findings provide exploratory, population-enriched signals of genetic susceptibility to TGCT in Hispanics. Altogether, they emphasize the critical need for more inclusive genomic research in underrepresented populations and provide a foundation for future investigations aimed at improving population-tailored risk assessment and prognostic tools.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 2","pages":"zcag007"},"PeriodicalIF":4.6,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147793360","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

MYC and AP-1 oncogenes cooperatively bind enhancers to rewire transcription. MYC和AP-1癌基因协同结合增强子进行重链转录。

IF 4.6

NAR cancer Pub Date : 2026-04-08 eCollection Date: 2026-06-01 DOI: 10.1093/narcan/zcag010

Reshma Kalyan Sundaram, Kshitiz Parihar, Stephanie Monson, Ravi Radhakrishnan, Bomyi Lim

{"title":"MYC and AP-1 oncogenes cooperatively bind enhancers to rewire transcription.","authors":"Reshma Kalyan Sundaram, Kshitiz Parihar, Stephanie Monson, Ravi Radhakrishnan, Bomyi Lim","doi":"10.1093/narcan/zcag010","DOIUrl":"10.1093/narcan/zcag010","url":null,"abstract":"The transcription factor c-MYC (MYC) is deregulated in ~70% of human cancers. Through de novo motif discovery analysis on published MYC ChIP-seq datasets from cancer cell lines, we found cell-type-specific co-enrichment of the TRE motifs (AP-1 binding sites) alongside MYC's canonical EBOX motif. MYC binds indirectly to TRE motifs in cooperation with AP-1 transcription factors, and these indirect interactions occur predominantly at enhancers rather than promoters. At elevated MYC levels, as seen in cancers, MYC's indirect binding to TRE sites at enhancers increases. Integration of ChIP-seq and RNA sequencing data revealed that TRE enhancer-binding sites are frequently associated with MYC-mediated transcriptional repression. Gene Ontology analysis showed that MYC utilizes TRE sites to transcriptionally rewire cells, modulating cancer hallmarks like proliferation, apoptosis, and cell adhesion. These molecular insights into how increased MYC levels alter gene regulation could inform new therapeutic strategies targeting cancer-specific MYC functions and its co-regulators.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 2","pages":"zcag010"},"PeriodicalIF":4.6,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13069683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147679806","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

Human DEAH-box helicase 8 regulates HSF1-mediated stress response and cancer-associated pre-mRNA splicing in tumour cells. 人DEAH-box解旋酶8调节肿瘤细胞中hsf1介导的应激反应和癌症相关的pre-mRNA剪接。

IF 4.6

NAR cancer Pub Date : 2026-03-12 eCollection Date: 2026-03-01 DOI: 10.1093/narcan/zcag008

Jennifer R Tall, Robert Te Poele, Alexandra Vasile, Pradeep Ramagiri, James Campbell, Caitlin R Davies, Marissa V Powers, Toby Roe, Deivendran Sankaran, Hannah Wang, Konstantinos Mitsopoulos, Bissan Al-Lazikani, Rob L M van Montfort, Emmanuel de Billy, Paul Workman, Paul A Clarke

{"title":"Human DEAH-box helicase 8 regulates HSF1-mediated stress response and cancer-associated pre-mRNA splicing in tumour cells.","authors":"Jennifer R Tall, Robert Te Poele, Alexandra Vasile, Pradeep Ramagiri, James Campbell, Caitlin R Davies, Marissa V Powers, Toby Roe, Deivendran Sankaran, Hannah Wang, Konstantinos Mitsopoulos, Bissan Al-Lazikani, Rob L M van Montfort, Emmanuel de Billy, Paul Workman, Paul A Clarke","doi":"10.1093/narcan/zcag008","DOIUrl":"10.1093/narcan/zcag008","url":null,"abstract":"Transcription factor heat shock factor 1 (HSF1) orchestrates the cellular stress response, promoting malignant transformation, unchecked proliferation, and stress-resilient survival of tumour cells. We set out to discover potentially druggable regulators of HSF1 activation and identified DEAH-box RNA helicase 8 (DHX8). We investigated the role of DHX8 in regulating HSF1 within the broader context of DHX8 function in cancer cells. DHX8 silencing induces intron retention in HSF1 transcripts, reducing HSF1 protein. Importantly, DHX8 loss significantly alters RNA processing of an HSF1-regulated cancer-associated gene signature linked to poor clinical outcomes, as well as additional oncogenic and stress-response pathways. DHX8 binds between the pre-messenger RNA (mRNA) lariat branch point and the 3' splice site, consistent with the predominance of intron-retained transcripts following DHX8 loss. We show that both the ATPase and RNA-binding activities of DHX8 are essential for its role in splicing, including processing of HSF1 mRNA. We also find that DHX8 silencing triggers apoptosis more effectively in human cancer cells than in non-tumorigenic cells. Our findings identify DHX8 as a critical regulator of stress-adaptive gene expression, highlighting its promise as a therapeutic target not only to disrupt HSF1-dependent transcriptional programs but also having broader effects in cancer cells under oncogenic stress.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 1","pages":"zcag008"},"PeriodicalIF":4.6,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12980071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147470673","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

Advancing inducible gene-inactivation systems to explore synthetic lethality. 推进诱导型基因失活系统探索合成致死率。

IF 4.6

NAR cancer Pub Date : 2026-02-23 eCollection Date: 2026-03-01 DOI: 10.1093/narcan/zcag004

Ádám Tamás Sánta, Alexandra Gráf, Katalin Vincze-Kontár, Katalin Kovács, Bernadett Bóna, Mónika Mórocz, Ernő Kiss, Lajos Haracska

{"title":"Advancing inducible gene-inactivation systems to explore synthetic lethality.","authors":"Ádám Tamás Sánta, Alexandra Gráf, Katalin Vincze-Kontár, Katalin Kovács, Bernadett Bóna, Mónika Mórocz, Ernő Kiss, Lajos Haracska","doi":"10.1093/narcan/zcag004","DOIUrl":"10.1093/narcan/zcag004","url":null,"abstract":"Synthetic lethality offers opportunities to identify therapeutic targets for cancer research, facilitating the development of targeted tumour therapy protocols. However, current gene knockout approaches may cause compensatory changes in cellular function and, often, RNAi does not align with the ideal time window for studies and can be inconsistent, limiting the study of molecular interactions, especially when the disruption of two genes causes cell death. To circumvent this problem, we developed the IGIS (Inducible Gene-Inactivation Systems) platform, which uses transient or targeted integration of tetracycline-regulated gene-silencing constructs into human cell lines and fluorescent markers, permitting precise timing of gene inactivation, avoiding transfection variability, and enabling follow-up assays. The applicability of the IGIS systems was validated by investigating the functional interplay between the BRCA1 and RAD18 genes. Combining IGIS with cell survival, DNA fibre, BrdU alkaline comet assays, and pRPA immunostaining, we show that BRCA1 and RAD18 work in different pathways in replication-fork restart and post-replicative gap filling, and thus combined loss of these factors leads to accumulation of ssDNA gaps and replication catastrophe. This synthetic-lethal interaction study with our newly developed IGIS method highlights RAD18-dependent tolerance mechanisms as potential therapeutic vulnerabilities in BRCA-deficient tumours.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 1","pages":"zcag004"},"PeriodicalIF":4.6,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12926718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147286877","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

Manipulating DNA repair and the DNA damage response to improve cancer therapy. 操纵DNA修复和DNA损伤反应以改善癌症治疗。

IF 4.6

NAR cancer Pub Date : 2026-02-18 eCollection Date: 2026-03-01 DOI: 10.1093/narcan/zcag006

Li Lan, Elise Fouquerel

引用次数: 0

Charting the multilevel molecular response to palbociclib in ER-positive breast cancer. 帕博西尼在er阳性乳腺癌中的多水平分子反应。

IF 4.6

NAR cancer Pub Date : 2026-02-17 eCollection Date: 2026-03-01 DOI: 10.1093/narcan/zcag003

Archishma Kavalipati, Amy Aponte, Michael E Sullivan, Sarah L Whittington, José C Martínez, Grant A Goda, Maria M Aleman, Michael J Emanuele, Daniel Dominguez

{"title":"Charting the multilevel molecular response to palbociclib in ER-positive breast cancer.","authors":"Archishma Kavalipati, Amy Aponte, Michael E Sullivan, Sarah L Whittington, José C Martínez, Grant A Goda, Maria M Aleman, Michael J Emanuele, Daniel Dominguez","doi":"10.1093/narcan/zcag003","DOIUrl":"10.1093/narcan/zcag003","url":null,"abstract":"The addition of CDK4/6 inhibitors to endocrine therapy has significantly improved outcomes in HR+/HER2- breast cancer (BC). However, variable patient responses and acquired resistance remain a clinical challenge. We therefore defined the comprehensive molecular response to palbociclib, the most clinically used CDK4/6 inhibitor. Global analyses of gene expression, protein abundance, splicing, and chromatin accessibility revealed broad patterns and specific changes that result from CDK4/6-inhibition in BC cells. We uncovered unexpected feedback between CDK4/6 and estrogen-response signaling, which has clear clinical implications. We also revealed a widespread alternative splicing program that partially overlapped with genes whose expression is regulated, and which is expected to impact protein function. These molecular changes nominated combination therapies that interfere with the activation of CDKs or ERα. Accordingly, co-targeting CDK7, which regulates CDK2, CDK4/6, and ERα, additively impacted cell fitness. Collectively, these data reveal a complex, multitiered response to CDK4/6 inhibition, with implications for therapeutic efficacy.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 1","pages":"zcag003"},"PeriodicalIF":4.6,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12910112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146222495","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

The RRM domains of PARP14 mediate replication fork degradation in BRCA2-deficient cells. PARP14的RRM结构域介导brca2缺陷细胞的复制叉降解。

IF 4.6

NAR cancer Pub Date : 2026-02-11 eCollection Date: 2026-03-01 DOI: 10.1093/narcan/zcag005

Anastasia Hale, Katie A Lynch, Ashna Dhoonmoon, Claudia M Nicolae, George-Lucian Moldovan

{"title":"The RRM domains of PARP14 mediate replication fork degradation in BRCA2-deficient cells.","authors":"Anastasia Hale, Katie A Lynch, Ashna Dhoonmoon, Claudia M Nicolae, George-Lucian Moldovan","doi":"10.1093/narcan/zcag005","DOIUrl":"10.1093/narcan/zcag005","url":null,"abstract":"Degradation of reversed replication forks by nucleases has emerged as a major mechanism of chemosensitivity in BRCA-deficient cells. We previously showed that the mono-ADP-ribosyltransferase PARP14 regulates MRE11 recruitment to reversed replication forks to promote their degradation. This results in genomic instability in BRCA-deficient cells. While it has been shown that PARP14-mediated recruitment of MRE11 to reversed forks promotes their degradation and collapse, how PARP14 binds to nascent DNA is unknown. Here, we show that, in BRCA-deficient cells, PARP14 is recruited to nascent DNA at reversed replication forks via its RRM (RNA Recognition Motifs) domains. We reveal that the RRM domains are necessary for the recruitment of MRE11 to reversed forks to promote nascent strand degradation at stalled replication forks in BRCA2-deficient cells. We also show that these domains are essential for replication stress-induced double-strand break formation in these cells. Our work furthers the understanding of nuclease recruitment and engagement at stalled forks to regulate genomic stability.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 1","pages":"zcag005"},"PeriodicalIF":4.6,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12891911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146184102","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

Differential roles of Rad18 in repressing carcinogen- and oncogene-driven mutagenesis in vivo. Rad18在体内抑制致癌物质和癌基因驱动的突变中的不同作用。

IF 4.6

NAR cancer Pub Date : 2026-01-19 eCollection Date: 2026-03-01 DOI: 10.1093/narcan/zcag001

Jay R Anand, Bethany Wagner Brown, Jitong Lou, Qisheng Gu, Yang Yang, Gaith Droby, Di Wu, Akankshya Jena, Jialiu Xie, Yuri Fedoriw, Bernard Weissman, Scott Williams, Cyrus Vaziri

{"title":"Differential roles of Rad18 in repressing carcinogen- and oncogene-driven mutagenesis in vivo.","authors":"Jay R Anand, Bethany Wagner Brown, Jitong Lou, Qisheng Gu, Yang Yang, Gaith Droby, Di Wu, Akankshya Jena, Jialiu Xie, Yuri Fedoriw, Bernard Weissman, Scott Williams, Cyrus Vaziri","doi":"10.1093/narcan/zcag001","DOIUrl":"10.1093/narcan/zcag001","url":null,"abstract":"The DNA repair protein RAD18 activates \"Y-family\" trans-lesion synthesis (TLS) DNA polymerases that are DNA damage-tolerant and potentially error-prone. RAD18 is also frequently overexpressed and pathologically activated in cancer cells. However, the extent to which RAD18 shapes cancer genomes and impacts tumorigenesis is unclear. Therefore, we tested the effect of Rad18 status on chemically induced and oncogene-driven tumorigenesis. In a chemically induced oral carcinogenesis model, acute (2-16 days) 4NQO treatment induces expression of Rad18 and TLS polymerase mRNAs in mouse oral epithelial cells prior to the emergence of oral squamous cell carcinomas (OSCCs). Chronic (8-week) 4NQO treatment leads to the onset of oral tumors that is accelerated in Rad18-/- mice when compared with Rad18+/+ animals. Analysis of OSCC exomes reveals increased levels of G(C)>T(A) transversions in Rad18-/- tumors when compared with Rad18+/+ . Therefore, Rad18 promotes error-free bypass of 4NQO-induced DNA lesions and suppresses 4NQO-induced oral carcinogenesis. In a KrasG12D -induced lung carcinogenesis model, Rad18 deficiency did not affect rates or incidence of oncogene-induced lung tumors or mutations. Taken together, we demonstrate that Rad18 has context-specific tumor-suppressive activity. Given the prevalence of 4NQO-like environmental exposures, RAD18 is highly likely to shape human cancer genomes and perhaps influence other aspects of the tumorigenic process.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 1","pages":"zcag001"},"PeriodicalIF":4.6,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12813500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014059","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