NAR cancer最新文献_第4页

An impaired ubiquitin-proteasome system increases APOBEC3A abundance. 泛素-蛋白酶体系统受损会增加 APOBEC3A 的丰度。

IF 3.4

NAR cancer Pub Date : 2023-12-19 eCollection Date: 2023-12-01 DOI: 10.1093/narcan/zcad058

Margo Coxon, Madeline A Dennis, Alexandra Dananberg, Christopher D Collins, Hannah E Wilson, Jordyn Meekma, Marina I Savenkova, Daniel Ng, Chelsea A Osbron, Tony M Mertz, Alan G Goodman, Sascha H Duttke, John Maciejowski, Steven A Roberts

{"title":"An impaired ubiquitin-proteasome system increases APOBEC3A abundance.","authors":"Margo Coxon, Madeline A Dennis, Alexandra Dananberg, Christopher D Collins, Hannah E Wilson, Jordyn Meekma, Marina I Savenkova, Daniel Ng, Chelsea A Osbron, Tony M Mertz, Alan G Goodman, Sascha H Duttke, John Maciejowski, Steven A Roberts","doi":"10.1093/narcan/zcad058","DOIUrl":"10.1093/narcan/zcad058","url":null,"abstract":"Apolipoprotein B messenger RNA (mRNA) editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases cause genetic instability during cancer development. Elevated APOBEC3A (A3A) levels result in APOBEC signature mutations; however, mechanisms regulating A3A abundance in breast cancer are unknown. Here, we show that dysregulating the ubiquitin-proteasome system with proteasome inhibitors, including Food and Drug Administration-approved anticancer drugs, increased A3A abundance in breast cancer and multiple myeloma cell lines. Unexpectedly, elevated A3A occurs via an ∼100-fold increase in A3A mRNA levels, indicating that proteasome inhibition triggers a transcriptional response as opposed to or in addition to blocking A3A degradation. This transcriptional regulation is mediated in part through FBXO22, a protein that functions in SKP1-cullin-F-box ubiquitin ligase complexes and becomes dysregulated during carcinogenesis. Proteasome inhibitors increased cellular cytidine deaminase activity, decreased cellular proliferation and increased genomic DNA damage in an A3A-dependent manner. Our findings suggest that proteasome dysfunction, either acquired during cancer development or induced therapeutically, could increase A3A-induced genetic heterogeneity and thereby influence therapeutic responses in patients.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"5 4","pages":"zcad058"},"PeriodicalIF":3.4,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10753533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139059395","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

Detection of oxaliplatin- and cisplatin-DNA lesions requires different global genome repair mechanisms that affect their clinical efficacy. 检测奥沙利铂和顺铂dna病变需要不同的全基因组修复机制，从而影响其临床疗效。

IF 3.4

NAR cancer Pub Date : 2023-12-05 eCollection Date: 2023-12-01 DOI: 10.1093/narcan/zcad057

Jana Slyskova, Alba Muniesa-Vargas, Israel Tojal da Silva, Rodrigo Drummond, Jiyeong Park, David Häckes, Isabella Poetsch, Cristina Ribeiro-Silva, Amandine Moretton, Petra Heffeter, Orlando D Schärer, Wim Vermeulen, Hannes Lans, Joanna I Loizou

{"title":"Detection of oxaliplatin- and cisplatin-DNA lesions requires different global genome repair mechanisms that affect their clinical efficacy.","authors":"Jana Slyskova, Alba Muniesa-Vargas, Israel Tojal da Silva, Rodrigo Drummond, Jiyeong Park, David Häckes, Isabella Poetsch, Cristina Ribeiro-Silva, Amandine Moretton, Petra Heffeter, Orlando D Schärer, Wim Vermeulen, Hannes Lans, Joanna I Loizou","doi":"10.1093/narcan/zcad057","DOIUrl":"10.1093/narcan/zcad057","url":null,"abstract":"The therapeutic efficacy of cisplatin and oxaliplatin depends on the balance between the DNA damage induction and the DNA damage response of tumor cells. Based on clinical evidence, oxaliplatin is administered to cisplatin-unresponsive cancers, but the underlying molecular causes for this tumor specificity are not clear. Hence, stratification of patients based on DNA repair profiling is not sufficiently utilized for treatment selection. Using a combination of genetic, transcriptomics and imaging approaches, we identified factors that promote global genome nucleotide excision repair (GG-NER) of DNA-platinum adducts induced by oxaliplatin, but not by cisplatin. We show that oxaliplatin-DNA lesions are a poor substrate for GG-NER initiating factor XPC and that DDB2 and HMGA2 are required for efficient binding of XPC to oxaliplatin lesions and subsequent GG-NER initiation. Loss of DDB2 and HMGA2 therefore leads to hypersensitivity to oxaliplatin but not to cisplatin. As a result, low DDB2 levels in different colon cancer cells are associated with GG-NER deficiency and oxaliplatin hypersensitivity. Finally, we show that colon cancer patients with low DDB2 levels have a better prognosis after oxaliplatin treatment than patients with high DDB2 expression. We therefore propose that DDB2 is a promising predictive marker of oxaliplatin treatment efficiency in colon cancer.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"5 4","pages":"zcad057"},"PeriodicalIF":3.4,"publicationDate":"2023-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138500566","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

Gene essentiality in cancer is better predicted by mRNA abundance than by gene regulatory network-inferred activity. 基因在癌症中的重要性通过mRNA丰度比通过基因调控网络推断的活性更好地预测。

IF 3.4

NAR cancer Pub Date : 2023-11-28 eCollection Date: 2023-12-01 DOI: 10.1093/narcan/zcad056

Cosmin Tudose, Jonathan Bond, Colm J Ryan

{"title":"Gene essentiality in cancer is better predicted by mRNA abundance than by gene regulatory network-inferred activity.","authors":"Cosmin Tudose, Jonathan Bond, Colm J Ryan","doi":"10.1093/narcan/zcad056","DOIUrl":"10.1093/narcan/zcad056","url":null,"abstract":"Gene regulatory networks (GRNs) are often deregulated in tumor cells, resulting in altered transcriptional programs that facilitate tumor growth. These altered networks may make tumor cells vulnerable to the inhibition of specific regulatory proteins. Consequently, the reconstruction of GRNs in tumors is often proposed as a means to identify therapeutic targets. While there are examples of individual targets identified using GRNs, the extent to which GRNs can be used to predict sensitivity to targeted intervention in general remains unknown. Here we use the results of genome-wide CRISPR screens to systematically assess the ability of GRNs to predict sensitivity to gene inhibition in cancer cell lines. Using GRNs derived from multiple sources, including GRNs reconstructed from tumor transcriptomes and from curated databases, we infer regulatory gene activity in cancer cell lines from ten cancer types. We then ask, in each cancer type, if the inferred regulatory activity of each gene is predictive of sensitivity to CRISPR perturbation of that gene. We observe slight variation in the correlation between gene regulatory activity and gene sensitivity depending on the source of the GRN and the activity estimation method used. However, we find that there is consistently a stronger relationship between mRNA abundance and gene sensitivity than there is between regulatory gene activity and gene sensitivity. This is true both when gene sensitivity is treated as a binary and a quantitative property. Overall, our results suggest that gene sensitivity is better predicted by measured expression than by GRN-inferred activity.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"5 4","pages":"zcad056"},"PeriodicalIF":3.4,"publicationDate":"2023-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10683780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138465247","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

Single-cell transcriptomics reveals long noncoding RNAs associated with tumor biology and the microenvironment in pancreatic cancer. 单细胞转录组学揭示了胰腺癌中与肿瘤生物学和微环境相关的长链非编码rna。

IF 3.4

NAR cancer Pub Date : 2023-11-22 eCollection Date: 2023-12-01 DOI: 10.1093/narcan/zcad055

Ha X Dang, Debanjan Saha, Reyka Jayasinghe, Sidi Zhao, Emily Coonrod, Jacqueline Mudd, S Peter Goedegebuure, Ryan Fields, Li Ding, Christopher A Maher

{"title":"Single-cell transcriptomics reveals long noncoding RNAs associated with tumor biology and the microenvironment in pancreatic cancer.","authors":"Ha X Dang, Debanjan Saha, Reyka Jayasinghe, Sidi Zhao, Emily Coonrod, Jacqueline Mudd, S Peter Goedegebuure, Ryan Fields, Li Ding, Christopher A Maher","doi":"10.1093/narcan/zcad055","DOIUrl":"10.1093/narcan/zcad055","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is highly heterogeneous and lethal. Long noncoding RNAs (lncRNAs) are an important class of genes regulating tumorigenesis and progression. Prior bulk transcriptomic studies in PDAC have revealed the dysregulation of lncRNAs but lack single-cell resolution to distinguish lncRNAs in tumor-intrinsic biology and the tumor microenvironment (TME). We analyzed single-cell transcriptome data from 73 multiregion samples in 21 PDAC patients to evaluate lncRNAs associated with intratumoral heterogeneity and the TME in PDAC. We found 111 cell-specific lncRNAs that reflected tumor, immune and stromal cell contributions, associated with outcomes, and validated across orthogonal datasets. Single-cell analysis of tumor cells revealed lncRNAs associated with TP53 mutations and FOLFIRINOX treatment that were obscured in bulk tumor analysis. Lastly, tumor subcluster analysis revealed widespread intratumor heterogeneity and intratumoral lncRNAs associated with cancer hallmarks and tumor processes such as angiogenesis, epithelial-mesenchymal transition, metabolism and immune signaling. Intratumoral subclusters and lncRNAs were validated across six datasets and showed clinically relevant associations with patient outcomes. Our study provides the first comprehensive assessment of the lncRNA landscape in PDAC using single-cell transcriptomic data and can serve as a resource, PDACLncDB (accessible at https://www.maherlab.com/pdaclncdb-overview), to guide future functional studies.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"5 4","pages":"zcad055"},"PeriodicalIF":3.4,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138465249","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

m⁶A epitranscriptome analysis reveals differentially methylated transcripts that drive early chemoresistance in bladder cancer. m6A表转录组分析揭示了膀胱癌早期化疗耐药的差异甲基化转录物。

NAR cancer Pub Date : 2023-11-16 eCollection Date: 2023-12-01 DOI: 10.1093/narcan/zcad054

Emmanuelle Hodara, Aubree Mades, Lisa Swartz, Maheen Iqbal, Tong Xu, Daniel Bsteh, Peggy J Farnham, Suhn K Rhie, Amir Goldkorn

{"title":"m6A epitranscriptome analysis reveals differentially methylated transcripts that drive early chemoresistance in bladder cancer.","authors":"Emmanuelle Hodara, Aubree Mades, Lisa Swartz, Maheen Iqbal, Tong Xu, Daniel Bsteh, Peggy J Farnham, Suhn K Rhie, Amir Goldkorn","doi":"10.1093/narcan/zcad054","DOIUrl":"10.1093/narcan/zcad054","url":null,"abstract":"N 6-Methyladenosine (m6A) RNA modifications dynamically regulate messenger RNA processing, differentiation and cell fate. Given these functions, we hypothesized that m6A modifications play a role in the transition to chemoresistance. To test this, we took an agnostic discovery approach anchored directly to chemoresistance rather than to any particular m6A effector protein. Specifically, we used methyl-RNA immunoprecipitation followed by sequencing (MeRIP-seq) in parallel with RNA sequencing to identify gene transcripts that were both differentially methylated and differentially expressed between cisplatin-sensitive and cisplatin-resistant bladder cancer (BC) cells. We filtered and prioritized these genes using clinical and functional database tools, and then validated several of the top candidates via targeted quantitative polymerase chain reaction (qPCR) and MeRIP-PCR. In cisplatin-resistant cells, SLC7A11 transcripts had decreased methylation associated with decreased m6A reader YTHDF3 binding, prolonged RNA stability, and increased RNA and protein levels, leading to reduced ferroptosis and increased survival. Consistent with this, cisplatin-sensitive BC cell lines and patient-derived organoids exposed to cisplatin for as little as 48 h exhibited similar mechanisms of SLC7A11 upregulation and chemoresistance, trends that were also reflected in public cancer survival databases. Collectively, these findings highlight epitranscriptomic plasticity as a mechanism of rapid chemoresistance and a potential therapeutic target.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"5 4","pages":"zcad054"},"PeriodicalIF":0.0,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10653028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138465248","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

Emerging roles of the CIP2A-TopBP1 complex in genome integrity. CIP2A-TopBP1复合物在基因组完整性中的新作用。

NAR cancer Pub Date : 2023-10-11 eCollection Date: 2023-12-01 DOI: 10.1093/narcan/zcad052

Henning Ummethum, Jiayi Li, Michael Lisby, Vibe H Oestergaard

引用次数: 0

Specificity of cancer-related chromosomal translocations is linked to proximity after the DNA double-strand break and subsequent selection. 癌症相关染色体易位的特异性与DNA双链断裂后的邻近性和随后的选择有关。

NAR cancer Pub Date : 2023-09-23 eCollection Date: 2023-09-01 DOI: 10.1093/narcan/zcad049

Reynand Jay Canoy, Anna Shmakova, Anna Karpukhina, Nikolai Lomov, Eugenia Tiukacheva, Yana Kozhevnikova, Franck André, Diego Germini, Yegor Vassetzky

{"title":"Specificity of cancer-related chromosomal translocations is linked to proximity after the DNA double-strand break and subsequent selection.","authors":"Reynand Jay Canoy, Anna Shmakova, Anna Karpukhina, Nikolai Lomov, Eugenia Tiukacheva, Yana Kozhevnikova, Franck André, Diego Germini, Yegor Vassetzky","doi":"10.1093/narcan/zcad049","DOIUrl":"10.1093/narcan/zcad049","url":null,"abstract":"Most cancer-related chromosomal translocations appear to be cell type specific. It is currently unknown why different chromosomal translocations occur in different cells. This can be due to either the occurrence of particular translocations in specific cell types or adaptive survival advantage conferred by translocations only in specific cells. We experimentally addressed this question by double-strand break (DSB) induction at MYC, IGH, AML and ETO loci in the same cell to generate chromosomal translocations in different cell lineages. Our results show that any translocation can potentially arise in any cell type. We have analyzed different factors that could affect the frequency of the translocations, and only the spatial proximity between gene loci after the DSB induction correlated with the resulting translocation frequency, supporting the 'breakage-first' model. Furthermore, upon long-term culture of cells with the generated chromosomal translocations, only oncogenic MYC-IGH and AML-ETO translocations persisted over a 60-day period. Overall, the results suggest that chromosomal translocation can be generated after DSB induction in any type of cell, but whether the cell with the translocation would persist in a cell population depends on the cell type-specific selective survival advantage that the chromosomal translocation confers to the cell.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"5 3","pages":"zcad049"},"PeriodicalIF":0.0,"publicationDate":"2023-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e3/ca/zcad049.PMC10518054.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41166037","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

INHAT subunit SET/TAF-Iβ regulates PRC1-independent H2AK119 mono-ubiquitination via E3 ligase MIB1 in colon cancer. INHAT亚单位SET/TAF-Iβ通过E3连接酶MIB1在癌症中调节PRC1依赖性H2AK119单泛素化。

NAR cancer Pub Date : 2023-09-22 eCollection Date: 2023-09-01 DOI: 10.1093/narcan/zcad050

Junyoung Park, Ji-Young Kim, Jin Woo Park, Joo Young Kang, Hyein Oh, Ja Young Hahm, Yun-Cheol Chae, Debabrata Chakravarti, Sang Beom Seo

{"title":"INHAT subunit SET/TAF-Iβ regulates PRC1-independent H2AK119 mono-ubiquitination via E3 ligase MIB1 in colon cancer.","authors":"Junyoung Park, Ji-Young Kim, Jin Woo Park, Joo Young Kang, Hyein Oh, Ja Young Hahm, Yun-Cheol Chae, Debabrata Chakravarti, Sang Beom Seo","doi":"10.1093/narcan/zcad050","DOIUrl":"https://doi.org/10.1093/narcan/zcad050","url":null,"abstract":"SET/TAF-Iβ, a subunit of the inhibitor of acetyltransferases (INHAT) complex, exhibits transcriptional repression activity by inhibiting histone acetylation. We find that SET/TAF-Iβ regulates mono-ubiquitination of histone H2A at lysine 119 (H2AK119ub), which is involved in polycomb-mediated transcriptional repression, in HCT116 cells. In this report, we demonstrate that SET/TAF-Iβ acts as an E2 ubiquitin-conjugating enzyme for PRC1-independent H2AK119ub. Furthermore, we identify that MIB1 is the E3 ligase partner for SET/TAF-Iβ using LC-MS/MS and in vitro ubiquitination assays. Transcriptome analysis reveals that SET/TAF-Iβ and MIB1 regulate the expression of genes related to DNA replication and cell cycle progression in HCT116 cells, and knockdown of either protein reduces proliferation of HCT116 cells by impeding cell cycle progression. Together, our study reveals a novel PRC1-independent epigenetic regulatory mechanism for H2AK119ub by SET/TAF-Iβ and MIB1 in colon cancer.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"5 3","pages":"zcad050"},"PeriodicalIF":0.0,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41161208","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

Comprehensive and realistic simulation of tumour genomic sequencing data. 肿瘤基因组测序数据的全面而现实的模拟。

NAR cancer Pub Date : 2023-09-22 eCollection Date: 2023-09-01 DOI: 10.1093/narcan/zcad051

Brian O'Sullivan, Cathal Seoighe

{"title":"Comprehensive and realistic simulation of tumour genomic sequencing data.","authors":"Brian O'Sullivan, Cathal Seoighe","doi":"10.1093/narcan/zcad051","DOIUrl":"10.1093/narcan/zcad051","url":null,"abstract":"Accurate identification of somatic mutations and allele frequencies in cancer has critical research and clinical applications. Several computational tools have been developed for this purpose but, in the absence of comprehensive 'ground truth' data, assessing the accuracy of these methods is challenging. We created a computational framework to simulate tumour and matched normal sequencing data for which the source of all loci that contain non-reference bases is known, based on a phased, personalized genome. Unlike existing methods, we account for sampling errors inherent in the sequencing process. Using this framework, we assess accuracy and biases in inferred mutations and their frequencies in an established somatic mutation calling pipeline. We demonstrate bias in existing methods of mutant allele frequency estimation and show, for the first time, the observed mutation frequency spectrum corresponding to a theoretical model of tumour evolution. We highlight the impact of quality filters on detection sensitivity of clinically actionable variants and provide definitive assessment of false positive and false negative mutation calls. Our simulation framework provides an improved means to assess the accuracy of somatic mutation calling pipelines and a detailed picture of the effects of technical parameters and experimental factors on somatic mutation calling in cancer samples.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"5 3","pages":"zcad051"},"PeriodicalIF":0.0,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41165532","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

GSK-3484862 targets DNMT1 for degradation in cells GSK-3484862靶向DNMT1降解细胞

NAR cancer Pub Date : 2022-11-04 DOI: 10.1101/2022.11.03.514954

Qin Chen, Yang Zeng, J. Hwang, Bigang Liu, Nan Dai, Ivan R. Corrêa, Marcos Estecio, Xing Zhang, Margarida Santos, Taiping Chen, Xiaodong Cheng

{"title":"GSK-3484862 targets DNMT1 for degradation in cells","authors":"Qin Chen, Yang Zeng, J. Hwang, Bigang Liu, Nan Dai, Ivan R. Corrêa, Marcos Estecio, Xing Zhang, Margarida Santos, Taiping Chen, Xiaodong Cheng","doi":"10.1101/2022.11.03.514954","DOIUrl":"https://doi.org/10.1101/2022.11.03.514954","url":null,"abstract":"Maintenance of genomic methylation patterns at DNA replication forks by DNMT1 is the key to faithful mitotic inheritance. DNMT1 is often overexpressed in cancer cells and the DNA hypomethylating agents azacytidine and decitabine are currently used in the treatment of hematologic malignancies. However, the toxicity of these cytidine analogs and their ineffectiveness in treating solid tumors have limited wider clinical use. GSK-3484862 is a newly-developed, dicyanopyridine containing, non-nucleoside DNMT1-selective inhibitor with low cellular toxicity. Here, we show that GSK-3484862 targets DNMT1 for protein degradation in both cancer cell lines and murine embryonic stem cells (mESCs). DNMT1 depletion was rapid, taking effect within hours following GSK-3484862 treatment, leading to global hypomethylation. Inhibitor-induced DNMT1 degradation was proteasome-dependent, with no discernible loss of DNMT1 mRNA. In mESCs, GSK-3484862-induced Dnmt1 degradation requires Uhrf1, an accessory factor of Dnmt1 with E3 ubiquitin ligase activity. We also show that Dnmt1 depletion and DNA hypomethylation induced by the compound are reversible after its removal. Together, these results indicate that this DNMT1-selective degrader/inhibitor will be a valuable tool for dissecting both coordinated events linking DNA methylation to gene expression and identifying downstream effectors that ultimately regulate cellular response to altered DNA methylation patterns in a tissue/cell-specific manner. Highlights GSK-3484862 targets DNMT1 for protein degradation in a wide-range of cancer cell lines, without a decrease in DNMT1 mRNA levels DNMT1 depletion leads to a >50% loss of global DNA methylation in cells within 2-days of treatment with GSK-3484862 GSK-3484862-induced DNMT1 degradation is proteasome-dependent In mESCs, Uhrf1 is required for GSK-3484862 to induce Dnmt1 degradation","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46018773","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: 3