4.8 Article

Oncogenic CDK13 mutations impede nuclear RNA surveillance

Journal

SCIENCE
Volume 380, Issue 6642, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abn7625

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RNA surveillance pathways detect and degrade defective transcripts to maintain RNA fidelity. Disruption of nuclear RNA surveillance is found to be oncogenic, with CDK13 mutation causing aberrant RNA stabilization and failed activation of nuclear RNA surveillance. Activating nuclear RNA surveillance is crucial to prevent the accumulation of aberrant RNAs and their consequences in development and disease.
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.

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