致癌突变会阻碍核 RNA 监测。
Oncogenic mutations impede nuclear RNA surveillance.
机构信息
Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
出版信息
Science. 2023 Apr 21;380(6642):eabn7625. doi: 10.1126/science.abn7625.
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 () is mutated in melanoma, and patient-mutated accelerates zebrafish melanoma. 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.
RNA 监控途径可检测和降解有缺陷的转录本，以确保 RNA 的保真度。我们发现，核 RNA 监控失调具有致癌性。细胞周期蛋白依赖性激酶 13 (CDK13) 在黑色素瘤中发生突变，而患者突变的 CDK13 可加速斑马鱼黑色素瘤的发生。CDK13 突变导致 RNA 异常稳定。CDK13 对于 ZC3H14 的磷酸化是必需的，这对于促进核 RNA 降解是必要且充分的。突变型 CDK13 无法激活核 RNA 监控，导致异常的蛋白编码转录本被稳定和翻译。强制异常 RNA 表达可加速斑马鱼中的黑色素瘤。我们在许多恶性肿瘤中发现编码核 RNA 监控成分的基因经常发生突变，从而确立了核 RNA 监控作为一种肿瘤抑制途径。激活核 RNA 监控对于避免异常 RNA 的积累及其在发育和疾病中的后续影响至关重要。
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