Oncogenic CDK13 Mutations Impede Nuclear RNA Surveillance [humanRibominusRNAseq]

RNA surveillance pathways detect and degrade defective transcripts to ensure RNA fidelity. We find 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 find 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. Overall design: 3' RNA-seq data from the A375 melanoma cell line with perturbations of genes encoding PAXT modulators

RNA监视通路可通过识别并降解缺陷转录本以维持RNA保真度。本研究发现核RNA监视通路失调具有致癌性。细胞周期蛋白依赖性激酶13（Cyclin Dependent Kinase 13，CDK13）在黑色素瘤中存在突变，且患者来源的突变型CDK13可加速斑马鱼黑色素瘤的进展。CDK13突变会导致异常RNA的稳定性异常升高。CDK13是ZC3H14磷酸化修饰所必需的，而该磷酸化修饰对于介导核RNA降解既是必要的，也是充分的。突变型CDK13无法激活核RNA监视通路，致使异常编码转录本的稳定性提升并得以翻译。人为过表达异常RNA可加速斑马鱼黑色素瘤的进展。我们在多种恶性肿瘤中均发现了编码核RNA监视通路组分的基因存在复发性突变，由此证实核RNA监视通路是一类肿瘤抑制通路。激活核RNA监视通路对于避免异常RNA的积累及其在发育与疾病中引发的后续不良后果至关重要。实验整体设计：来自经PAXT调控因子编码基因扰动处理的A375黑色素瘤细胞系的3'端RNA测序（RNA-seq）数据。