IF 3.4

NAR cancer Pub Date : 2024-09-26 eCollection Date: 2024-09-01 DOI: 10.1093/narcan/zcae037

Rachel Shoemaker, Mo-Fan Huang, Ying-Si Wu, Cheng-Shuo Huang, Dung-Fang Lee

{"title":"Decoding the molecular symphony: interactions between the m6A and p53 signaling pathways in cancer.","authors":"Rachel Shoemaker, Mo-Fan Huang, Ying-Si Wu, Cheng-Shuo Huang, Dung-Fang Lee","doi":"10.1093/narcan/zcae037","DOIUrl":"https://doi.org/10.1093/narcan/zcae037","url":null,"abstract":"The p53 tumor suppressor gene governs a multitude of complex cellular processes that are essential for anti-cancer function and whose dysregulation leads to aberrant gene transcription, activation of oncogenic signaling and cancer development. Although mutations can occur at any point in the genetic sequence, missense mutations comprise the majority of observed p53 mutations in cancers regardless of whether the mutation is germline or somatic. One biological process involved in both mutant and wild-type p53 signaling is the N 6-methyladenosine (m6A) epitranscriptomic network, a type of post-transcriptional modification involved in over half of all eukaryotic mRNAs. Recently, a significant number of findings have demonstrated unique interactions between p53 and the m6A epitranscriptomic network in a variety of cancer types, shedding light on a previously uncharacterized connection that causes significant dysregulation. Cross-talk between wild-type or mutant p53 and the m6A readers, writers and erasers has been shown to impact cellular function and induce cancer formation by influencing various cancer hallmarks. Here, this review aims to summarize the complex interplay between the m6A epitranscriptome and p53 signaling pathway, highlighting its effects on tumorigenesis and other hallmarks of cancer, as well as identifying its therapeutic implications for the future.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335463","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

Novel insights into the role of bisphenol A (BPA) in genomic instability. 关于双酚 A (BPA) 在基因组不稳定性中作用的新见解。

IF 3.4

NAR cancer Pub Date : 2024-09-24 eCollection Date: 2024-09-01 DOI: 10.1093/narcan/zcae038

Anastasia Hale, George-Lucian Moldovan

引用次数: 0

Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation. TIMELESS 单倍体缺失可模拟 PARG 抑制剂的内在敏感性，并通过补充核苷来挽救这种敏感性。

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

FBXO42 activity is required to prevent mitotic arrest, spindle assembly checkpoint activation and lethality in glioblastoma and other cancers. 在胶质母细胞瘤和其他癌症中，FBXO42 的活性是防止有丝分裂停滞、纺锤体组装检查点激活和致死所必需的。

IF 3.4

NAR cancer Pub Date : 2024-05-20 eCollection Date: 2024-06-01 DOI: 10.1093/narcan/zcae021

Pia Hoellerbauer, Megan Kufeld, Sonali Arora, Kelly Mitchell, Emily J Girard, Jacob A Herman, James M Olson, Patrick J Paddison

{"title":"FBXO42 activity is required to prevent mitotic arrest, spindle assembly checkpoint activation and lethality in glioblastoma and other cancers.","authors":"Pia Hoellerbauer, Megan Kufeld, Sonali Arora, Kelly Mitchell, Emily J Girard, Jacob A Herman, James M Olson, Patrick J Paddison","doi":"10.1093/narcan/zcae021","DOIUrl":"10.1093/narcan/zcae021","url":null,"abstract":"Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. To identify genes differentially required for the viability of GBM stem-like cells (GSCs), we performed functional genomic lethality screens comparing GSCs and control human neural stem cells. Among top-scoring hits in a subset of GBM cells was the F-box-containing gene FBXO42, which was also predicted to be essential in ∼15% of cell lines derived from a broad range of cancers. Mechanistic studies revealed that, in sensitive cells, FBXO42 activity prevents chromosome alignment defects, mitotic cell cycle arrest and cell death. The cell cycle arrest, but not the cell death, triggered by FBXO42 inactivation could be suppressed by brief exposure to a chemical inhibitor of Mps1, a key spindle assembly checkpoint (SAC) kinase. FBXO42's cancer-essential function requires its F-box and Kelch domains, which are necessary for FBXO42's substrate recognition and targeting by SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex. However, none of FBXO42's previously proposed targets, including ING4, p53 and RBPJ, were responsible for the observed phenotypes. Instead, our results suggest that FBOX42 alters the activity of one or more proteins that perturb chromosome-microtubule dynamics in cancer cells, which in turn leads to induction of the SAC and cell death.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141077501","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 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

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