The RNA surveillance pathway can detect and interpret defective transcripts to ensure the fidelity of RNA. Recently, in a research report entitled “Oncogenic CDK13 mutations infinite nuclear RNA surveillance” published on the international journal Science, scientists from Howard Hughes Medical Research Institute and other institutions found a new mechanism that affects the occurrence of melanoma through research, which has a very broad and important significance for the treatment of multiple cancer patients.
In the article, researchers focused on studying a protein called CDK13, which was previously unclear about its important role in cancer development. Insco, the researcher, said that we found that CDK13 protein can play the role of tumor suppressor in melanoma, and its mutation or deletion will lead to the occurrence of tumors. By analyzing the data of melanoma patients and the Zon zebrafish model, the researchers clarified the causes of CDK13 protein deletion or mutation, and revealed the molecular mechanism that led to cancer, including the underlying gene expression.
Cells often make mistakes in gene expression. Researchers found that cells will produce shortened RNAs, and then produce abnormal proteins that can induce cancer. Fortunately, cells have an active cleaning mechanism to deal with these transcription errors. But if cells cannot remove this garbage, these RNAs will accumulate and become carcinogens. In the article, researchers pointed out that mutated CDK13 may be why abnormal RNAs cannot be eliminated.
Under normal circumstances, CDK13 can swim around the cell and supervise RNA. If it encounters abnormal RNA, it will recruit a series of proteins to work together (protein complex) to degrade short-chain RNA in the nucleus. Essentially, it will use a “vacuum cleaner” to remove errors and precancerous substances in the cell. But if a mutation occurs, CDK13 will no longer be able to fulfill its RNA supervision function and will basically eliminate garbage. We all know that these garbage RNAs cause cancer, because when placed in zebrafish, they will reflect the entire process again.
CDK13 mutation exists in many human cancers and has the same function in zebrafish, mice, and human cells. Researchers have observed the mutant CDK13 in patients’ melanoma tissues, and observed that it will accelerate the growth of melanoma in zebrafish studies. In addition, the researchers also discovered other significance of CDK13 mutations involving the PAXT complex, which may be the first step in nuclear RNA degradation. Researcher Insco explained that it may serve as a labeling mechanism, but if CDK13 mutates, the PAXT complex will not be activated, which acts like a switch that can turn on or off the ‘vacuum cleaner’.
This latest study reveals that damaged RNAs may be actively regulated, which indicates that they will have an impact on the pathogenesis of cancer in many patients. However, in melanoma alone, more than 20% of patients carry this CDK13-designed broken nuclear RNA monitoring mechanism. This research discovery shows that the mutation of CDK13 in human cancer may reveal that it is widely involved in the mechanism of cancer occurrence. Along with CDK13, at least two other members of the PAXT complex will frequently mutate in a variety of cancer types, not just melanoma. Researchers believe that this is not just about CDK13, but perhaps multiple other complex members are also involved in this fragmentation process.
Based on this research work, later researchers will continue to study better to understand the RNA supervision mechanism of the nucleus and provide new treatment methods for melanoma patients who cannot respond to the current treatment. Researchers will also study deeper into RNA biology, as it may be directly related to the occurrence of tumors. In summary, in this study, researchers found that in many malignant tumors, genes encoding nuclear RNA supervisory components undergo repeated mutations, thus determining that nuclear RNA supervision can serve as a tumor suppressor pathway. Activating the nuclear RNA supervision mechanism may be crucial for avoiding the accumulation of abnormal RNAs and their subsequent consequences during the development and disease occurrence of the body.
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Reference
MEGAN L. INSCO,BRIAN J. ABRAHAM,SARA J. DUBBURY, et al. Oncogenic CDK13 mutations impede nuclear RNA surveillance, Science (2023). DOI:10.1126/science.abn7625