دورية أكاديمية
Anticancer benzoxaboroles block pre-mRNA processing by directly inhibiting CPSF3.
| العنوان: | Anticancer benzoxaboroles block pre-mRNA processing by directly inhibiting CPSF3. |
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| المؤلفون: | Tao Y; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Budhipramono A; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Huang J; Department of Biological Sciences, Columbia University, New York, NY 10027, USA., Fang M; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Xie S; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Kim J; Quantitative Biomedical Research Center, Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Khivansara V; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, Program in Molecular Medicine and Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Dominski Z; Department of Biochemistry and Biophysics and Integrative Program in Biological and Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA., Tong L; Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: ltong@columbia.edu., De Brabander JK; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: jef.debrabander@utsouthwestern.edu., Nijhawan D; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, Program in Molecular Medicine and Division of Hematology/Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: deepak.nijhawan@utsouthwestern.edu. |
| المصدر: | Cell chemical biology [Cell Chem Biol] 2024 Jan 18; Vol. 31 (1), pp. 139-149.e14. Date of Electronic Publication: 2023 Nov 14. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101676030 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2451-9448 (Electronic) Linking ISSN: 24519448 NLM ISO Abbreviation: Cell Chem Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Cambridge, MA : Cell Press, 2016- |
| مواضيع طبية MeSH: | Cleavage And Polyadenylation Specificity Factor*/antagonists & inhibitors , Cleavage And Polyadenylation Specificity Factor*/chemistry , Endonucleases*/antagonists & inhibitors , RNA Precursors*/genetics , RNA Precursors*/metabolism , Boron Compounds*/chemistry , Boron Compounds*/pharmacology , Antineoplastic Agents*/chemistry , Antineoplastic Agents*/pharmacology , RNA Processing, Post-Transcriptional*/drug effects, Humans ; Cell Line, Tumor |
| مستخلص: | A novel class of benzoxaboroles was reported to induce cancer cell death but the mechanism was unknown. Using a forward genetics platform, we discovered mutations in cleavage and polyadenylation specific factor 3 (CPSF3) that reduce benzoxaborole binding and confer resistance. CPSF3 is the endonuclease responsible for pre-mRNA 3'-end processing, which is also important for RNA polymerase II transcription termination. Benzoxaboroles inhibit this endonuclease activity of CPSF3 in vitro and also curb transcriptional termination in cells, which results in the downregulation of numerous constitutively expressed genes. Furthermore, we used X-ray crystallography to demonstrate that benzoxaboroles bind to the active site of CPSF3 in a manner distinct from the other known inhibitors of CPSF3. The benzoxaborole compound impeded the growth of cancer cell lines derived from different lineages. Our results suggest benzoxaboroles may represent a promising lead as CPSF3 inhibitors for clinical development. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 Elsevier Ltd. All rights reserved.) |
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| معلومات مُعتمدة: | P30 GM124165 United States GM NIGMS NIH HHS; R35 GM118093 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | 0 (Cleavage And Polyadenylation Specificity Factor) EC 3.1.- (Endonucleases) 0 (RNA Precursors) 0 (Boron Compounds) 0 (Antineoplastic Agents) 0 (CPSF3 protein, human) |
| تواريخ الأحداث: | Date Created: 20231115 Date Completed: 20240202 Latest Revision: 20240212 |
| رمز التحديث: | 20240213 |
| مُعرف محوري في PubMed: | PMC10841686 |
| DOI: | 10.1016/j.chembiol.2023.10.019 |
| PMID: | 37967558 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2451-9448 |
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| DOI: | 10.1016/j.chembiol.2023.10.019 |