Oncogenic CDK13 mutations impede nuclear RNA surveillance

• 成果类型: Article
• 署名作者: Insco, Megan L.; Abraham, Brian J.; Dubbury, Sara J.; Kaltheuner, Ines H.; Dust, Sofia; Wu, Constance; Chen, Kevin Y.; Liu, David; Bellaousov, Stanislav; Cox, Anna M.; Martin, Benjamin J. E.; Zhang, Tongwu; Ludwig, Calvin G.; Fabo, Tania; Modhurima, Rodsy; Esgdaille, Dakarai E.; Henriques, Telmo; Brown, Kevin M.; Chanock, Stephen J.; Geyer, Matthias; Adelman, Karen; Sharp, Phillip A.; Young, Richard A.; Boutz, Paul L.; Zon, Leonard I.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; St Jude Children's Research Hospital; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); University of Bonn; University of Rochester; Harvard University; Harvard Medical School; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); NIH National Cancer Institute- Division of Cancer Epidemiology & Genetics; Massachusetts Institute of Technology (MIT); Whitehead Institute; University of Rochester; University of Rochester
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13137
• DOI: 10.1126/science.abn7625
• 发表日期: 2023-04-21
• 关键词: binding protein; ctla-4 blockade; terminal domain; messenger-rna; transcription; cdk7; expression; phosphorylation; CLASSIFICATION; inhibition

摘要

RNA surveillance pathways detect and degrade defective transcripts to ensure RNA fidelity. We found that disrupted nuclear RNA surveillance is oncogenic. Cyclin-dependent kinase 13 (CDK13) is mutated in melanoma, and patient-mutated CDK13 accelerates zebrafish melanoma. CDK13 mutation causes aberrant RNA stabilization. CDK13 is required for ZC3H14 phosphorylation, which is necessary and sufficient to promote nuclear RNA degradation. Mutant CDK13 fails to activate nuclear RNA surveillance, causing aberrant protein-coding transcripts to be stabilized and translated. Forced aberrant RNA expression accelerates melanoma in zebrafish. We found recurrent mutations in genes encoding nuclear RNA surveillance components in many malignancies, establishing nuclear RNA surveillance as a tumor -suppressive pathway. Activating nuclear RNA surveillance is crucial to avoid accumulation of aberrant RNAs and their ensuing consequences in development and disease.