IF 3.4

NAR cancer Pub Date : 2024-07-16 eCollection Date: 2024-09-01 DOI: 10.1093/narcan/zcae030

Camilla Coulson-Gilmer, Samantha Littler, Bethany M Barnes, Rosie M Brady, Holda A Anagho, Nisha Pillay, Malini Dey, William Macmorland, Daniel Bronder, Louisa Nelson, Anthony Tighe, Wei-Hsiang Lin, Robert D Morgan, Richard D Unwin, Michael L Nielsen, Joanne C McGrail, Stephen S Taylor

{"title":"Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation.","authors":"Camilla Coulson-Gilmer, Samantha Littler, Bethany M Barnes, Rosie M Brady, Holda A Anagho, Nisha Pillay, Malini Dey, William Macmorland, Daniel Bronder, Louisa Nelson, Anthony Tighe, Wei-Hsiang Lin, Robert D Morgan, Richard D Unwin, Michael L Nielsen, Joanne C McGrail, Stephen S Taylor","doi":"10.1093/narcan/zcae030","DOIUrl":"10.1093/narcan/zcae030","url":null,"abstract":"A subset of cancer cells are intrinsically sensitive to inhibitors targeting PARG, the poly(ADP-ribose) glycohydrolase that degrades PAR chains. Sensitivity is accompanied by persistent DNA replication stress, and can be induced by inhibition of TIMELESS, a replisome accelerator. However, the nature of the vulnerability responsible for intrinsic sensitivity remains undetermined. To understand PARG activity dependency, we analysed Timeless model systems and intrinsically sensitive ovarian cancer cells. We show that nucleoside supplementation rescues all phenotypes associated with PARG inhibitor sensitivity, including replisome speed and fork stalling, S-phase completion and mitotic entry, proliferation dynamics and clonogenic potential. Importantly nucleoside supplementation restores PARG inhibitor resistance despite the continued presence of PAR chains, indicating that sensitivity does not correlate with PAR levels. In addition, we show that inhibition of thymidylate synthase, an enzyme required for dNTP homeostasis, induces PARG-dependency. Together, these observations suggest that PARG inhibitor sensitivity reflects an inability to control replisome speed and/or maintain helicase-polymerase coupling in response to nucleotide imbalances.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11249981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141629663","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

CRISPR-Cas9 for selective targeting of somatic mutations in pancreatic cancers. 用于选择性靶向胰腺癌体细胞突变的 CRISPR-Cas9。

IF 3.4

NAR cancer Pub Date : 2024-06-19 eCollection Date: 2024-06-01 DOI: 10.1093/narcan/zcae028

Selina Shiqing K Teh, Kirsten Bowland, Eitan Halper-Stromberg, Akhil Kotwal, Alexis Bennett, Alyza Skaist, Jacqueline Tang, Fidel Cai, Antonella Macoretta, Hong Liang, Hirohiko Kamiyama, Sarah Wheelan, Ming-Tseh Lin, Ralph H Hruban, Chien-Fu Hung, Michael Goldstein, Robert B Scharpf, Nicholas J Roberts, James R Eshleman

{"title":"CRISPR-Cas9 for selective targeting of somatic mutations in pancreatic cancers.","authors":"Selina Shiqing K Teh, Kirsten Bowland, Eitan Halper-Stromberg, Akhil Kotwal, Alexis Bennett, Alyza Skaist, Jacqueline Tang, Fidel Cai, Antonella Macoretta, Hong Liang, Hirohiko Kamiyama, Sarah Wheelan, Ming-Tseh Lin, Ralph H Hruban, Chien-Fu Hung, Michael Goldstein, Robert B Scharpf, Nicholas J Roberts, James R Eshleman","doi":"10.1093/narcan/zcae028","DOIUrl":"10.1093/narcan/zcae028","url":null,"abstract":"Somatic mutations are desirable targets for selective elimination of cancer, yet most are found within noncoding regions. We have adapted the CRISPR-Cas9 gene editing tool as a novel, cancer-specific killing strategy by targeting the subset of somatic mutations that create protospacer adjacent motifs (PAMs), which have evolutionally allowed bacterial cells to distinguish between self and non-self DNA for Cas9-induced double strand breaks. Whole genome sequencing (WGS) of paired tumor minus normal (T-N) samples from three pancreatic cancer patients (Panc480, Panc504, and Panc1002) showed an average of 417 somatic PAMs per tumor produced from single base substitutions. Further analyses of 591 paired T-N samples from The International Cancer Genome Consortium found medians of ∼455 somatic PAMs per tumor in pancreatic, ∼2800 in lung, and ∼3200 in esophageal cancer cohorts. Finally, we demonstrated 69-99% selective cell death of three targeted pancreatic cancer cell lines using 4-9 sgRNAs designed using the somatic PAM discovery approach. We also showed no off-target activity from these tumor-specific sgRNAs in either the patient's normal cells or an irrelevant cancer using WGS. This study demonstrates the potential of CRISPR-Cas9 as a novel and selective anti-cancer strategy, and supports the genetic targeting of adult cancers.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11195629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141447921","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

Microsatellite break-induced replication generates highly mutagenized extrachromosomal circular DNAs. 微卫星断裂诱导复制产生高度突变的染色体外环状DNA。

IF 3.4

NAR cancer Pub Date : 2024-06-08 eCollection Date: 2024-06-01 DOI: 10.1093/narcan/zcae027

Rujuta Yashodhan Gadgil, S Dean Rider, Resha Shrestha, Venicia Alhawach, David C Hitch, Michael Leffak

{"title":"Microsatellite break-induced replication generates highly mutagenized extrachromosomal circular DNAs.","authors":"Rujuta Yashodhan Gadgil, S Dean Rider, Resha Shrestha, Venicia Alhawach, David C Hitch, Michael Leffak","doi":"10.1093/narcan/zcae027","DOIUrl":"10.1093/narcan/zcae027","url":null,"abstract":"Extrachromosomal circular DNAs (eccDNAs) are produced from all regions of the eucaryotic genome. We used inverse PCR of non-B microsatellites capable of forming hairpin, triplex, quadruplex and AT-rich structures integrated at a common ectopic chromosomal site to show that these non-B DNAs generate highly mutagenized eccDNAs by replication-dependent mechanisms. Mutagenesis occurs within the non-B DNAs and extends several kilobases bidirectionally into flanking and nonallelic DNA. Each non-B DNA exhibits a different pattern of mutagenesis, while sister clones containing the same non-B DNA also display distinct patterns of recombination, microhomology-mediated template switching and base substitutions. Mutations include mismatches, short duplications, long nontemplated insertions, large deletions and template switches to sister chromatids and nonallelic chromosomes. Drug-induced replication stress or the depletion of DNA repair factors Rad51, the COPS2 signalosome subunit or POLη change the pattern of template switching and alter the eccDNA mutagenic profiles. We propose an asynchronous capture model based on break-induced replication from microsatellite-induced DNA double strand breaks to account for the generation and circularization of mutagenized eccDNAs and the appearance of genomic homologous recombination deficiency (HRD) scars. These results may help to explain the appearance of tumor eccDNAS and their roles in neoantigen production, oncogenesis and resistance to chemotherapy.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11161834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141297689","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 shaping of mRNA translation plasticity by RNA G-quadruplexes in cancer progression and therapy resistance. 在癌症进展和抗药性过程中，RNA G-四联体对 mRNA 翻译可塑性的影响。

NAR cancer Pub Date : 2024-05-31 eCollection Date: 2024-06-01 DOI: 10.1093/narcan/zcae025

Anne Cammas, Alice Desprairies, Erik Dassi, Stefania Millevoi

引用次数: 0

Non-canonical mRNA translation initiation in cell stress and cancer. 细胞应激和癌症中的非规范 mRNA 翻译启动

NAR cancer Pub Date : 2024-05-31 eCollection Date: 2024-06-01 DOI: 10.1093/narcan/zcae026

Mélanie Mahé, Tiffany Rios-Fuller, Olga Katsara, Robert J Schneider

{"title":"Non-canonical mRNA translation initiation in cell stress and cancer.","authors":"Mélanie Mahé, Tiffany Rios-Fuller, Olga Katsara, Robert J Schneider","doi":"10.1093/narcan/zcae026","DOIUrl":"10.1093/narcan/zcae026","url":null,"abstract":"The now well described canonical mRNA translation initiation mechanism of m7G 'cap' recognition by cap-binding protein eIF4E and assembly of the canonical pre-initiation complex consisting of scaffolding protein eIF4G and RNA helicase eIF4A has historically been thought to describe all cellular mRNA translation. However, the past decade has seen the discovery of alternative mechanisms to canonical eIF4E mediated mRNA translation initiation. Studies have shown that non-canonical alternate mechanisms of cellular mRNA translation initiation, whether cap-dependent or independent, serve to provide selective translation of mRNAs under cell physiological and pathological stress conditions. These conditions typically involve the global downregulation of canonical eIF4E1/cap-mediated mRNA translation, and selective translational reprogramming of the cell proteome, as occurs in tumor development and malignant progression. Cancer cells must be able to maintain physiological plasticity to acquire a migratory phenotype, invade tissues, metastasize, survive and adapt to severe microenvironmental stress conditions that involve inhibition of canonical mRNA translation initiation. In this review we describe the emerging, important role of non-canonical, alternate mechanisms of mRNA translation initiation in cancer, particularly in adaptation to stresses and the phenotypic cell fate changes involved in malignant progression and metastasis. These alternate translation initiation mechanisms provide new targets for oncology therapeutics development.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11140632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141201327","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

Upstream open reading frames: new players in the landscape of cancer gene regulation. 上游开放阅读框：癌症基因调控格局中的新角色。

NAR cancer Pub Date : 2024-05-20 eCollection Date: 2024-06-01 DOI: 10.1093/narcan/zcae023

Anwesha Dasgupta, John R Prensner

引用次数: 0

The impact of ribosome biogenesis in cancer: from proliferation to metastasis 核糖体生物发生对癌症的影响：从增殖到转移

NAR cancer Pub Date : 2024-04-15 DOI: 10.1093/narcan/zcae017

Sseu-Pei Hwang, C. Denicourt

{"title":"The impact of ribosome biogenesis in cancer: from proliferation to metastasis","authors":"Sseu-Pei Hwang, C. Denicourt","doi":"10.1093/narcan/zcae017","DOIUrl":"https://doi.org/10.1093/narcan/zcae017","url":null,"abstract":"Abstract The dysregulation of ribosome biogenesis is a hallmark of cancer, facilitating the adaptation to altered translational demands essential for various aspects of tumor progression. This review explores the intricate interplay between ribosome biogenesis and cancer development, highlighting dynamic regulation orchestrated by key oncogenic signaling pathways. Recent studies reveal the multifaceted roles of ribosomes, extending beyond protein factories to include regulatory functions in mRNA translation. Dysregulated ribosome biogenesis not only hampers precise control of global protein production and proliferation but also influences processes such as the maintenance of stem cell-like properties and epithelial-mesenchymal transition, contributing to cancer progression. Interference with ribosome biogenesis, notably through RNA Pol I inhibition, elicits a stress response marked by nucleolar integrity loss, and subsequent G1-cell cycle arrest or cell death. These findings suggest that cancer cells may rely on heightened RNA Pol I transcription, rendering ribosomal RNA synthesis a potential therapeutic vulnerability. The review further explores targeting ribosome biogenesis vulnerabilities as a promising strategy to disrupt global ribosome production, presenting therapeutic opportunities for cancer treatment.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140701350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CSDE1: a versatile regulator of gene expression in cancer CSDE1：癌症基因表达的多功能调节器

NAR cancer Pub Date : 2024-04-10 DOI: 10.1093/narcan/zcae014

Annagiulia Ciocia, N. Mestre-Farràs, Ignacio Vicent-Nacht, Tanit Guitart, Fátima Gebauer

引用次数: 0

HDAC10 inhibition represses melanoma cell growth and BRAF inhibitor resistance via upregulating SPARC expression 抑制 HDAC10 可通过上调 SPARC 的表达抑制黑色素瘤细胞的生长和 BRAF 抑制剂的抗药性

NAR cancer Pub Date : 2024-04-08 DOI: 10.1093/narcan/zcae018

Hongbo Ling, Yixuan Li, Changmin Peng, Shengyu Yang, Edward Seto

{"title":"HDAC10 inhibition represses melanoma cell growth and BRAF inhibitor resistance via upregulating SPARC expression","authors":"Hongbo Ling, Yixuan Li, Changmin Peng, Shengyu Yang, Edward Seto","doi":"10.1093/narcan/zcae018","DOIUrl":"https://doi.org/10.1093/narcan/zcae018","url":null,"abstract":"Abstract Secreted protein acidic and rich in cysteine (SPARC), a conserved secreted glycoprotein, plays crucial roles in regulating various biological processes. SPARC is highly expressed and has profound implications in several cancer types, including melanoma. Understanding the mechanisms that govern SPARC expression in cancers has the potential to lead to improved cancer diagnosis, prognosis, treatment strategies, and patient outcomes. Here, we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator of SPARC expression in melanoma cells. Depletion or inhibition of HDAC10 upregulates SPARC expression, whereas overexpression of HDAC10 downregulates it. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the state of acetylation of histone H3 at lysine 27 (H3K27ac) at SPARC regulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby fine-tuning SPARC transcription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth primarily by activating AMPK signaling and inducing autophagy. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitization of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through indirect histone modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140729495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities 子宫内膜癌的 DNA 损伤反应 (DDR) 情况定义了不同的疾病亚型，并揭示了治疗机会

NAR cancer Pub Date : 2024-04-08 DOI: 10.1093/narcan/zcae015

Xingyuan Zhang, Sayali Joseph, Di Wu, Jessica L. Bowser, Cyrus Vaziri

{"title":"The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities","authors":"Xingyuan Zhang, Sayali Joseph, Di Wu, Jessica L. Bowser, Cyrus Vaziri","doi":"10.1093/narcan/zcae015","DOIUrl":"https://doi.org/10.1093/narcan/zcae015","url":null,"abstract":"Abstract Genome maintenance is an enabling characteristic that allows neoplastic cells to tolerate the inherent stresses of tumorigenesis and evade therapy-induced genotoxicity. Neoplastic cells also deploy many mis-expressed germ cell proteins termed Cancer Testes Antigens (CTAs) to promote genome maintenance and survival. Here, we present the first comprehensive characterization of the DNA Damage Response (DDR) and CTA transcriptional landscapes of endometrial cancer in relation to conventional histological and molecular subtypes. We show endometrial serous carcinoma (ESC), an aggressive endometrial cancer subtype, is defined by gene expression signatures comprising members of the Replication Fork Protection Complex (RFPC) and Fanconi Anemia (FA) pathway and CTAs with mitotic functions. DDR and CTA-based profiling also defines a subset of highly aggressive endometrioid endometrial carcinomas (EEC) with poor clinical outcomes that share similar profiles to ESC yet have distinct characteristics based on conventional histological and genomic features. Using an unbiased CRISPR-based genetic screen and a candidate gene approach, we confirm that DDR and CTA genes that constitute the ESC and related EEC gene signatures are required for proliferation and therapy-resistance of cultured endometrial cancer cells. Our study validates the use of DDR and CTA-based tumor classifiers and reveals new vulnerabilities of aggressive endometrial cancer where none currently exist.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140729240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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