Unveiling a novel cancer mechanism: CDK13 mutations hinder RNA surveillance

This groundbreaking discovery was published in the journal Science on April 21. It has broad implications because this mechanism seems to be present across various malignancies. The findings could potentially unlock a new range of molecules that cancer drugs can target.

The gene at the center of this research is CDK13. It was initially identified by Megan Insco, an instructor in medicine at HMS and former research fellow in the lab of Leonard Zon at HMS and Boston Children's.

Insco's investigations involving zebrafish revealed that mutations in CDK13 accelerated melanoma development. Astonishingly, similar mutations were also found in numerous human melanomas.

However, the true surprise is in understanding how the CDK13 mutation causes cancer. Insco observed multiple short, defective RNA molecules produced by melanoma cells. It was an abnormality, and she promptly shared it with Zon. 

The role of the CDK13 Mutation in cancer

Zon is a professor of stem cell and regenerative biology at Harvard University and director of the Stem Cell Research Program at Boston Children. Recognizing the significance of the finding, he remarked, "I said, 'That definitely is interesting.' It took years to figure out what it meant." Normally, cells produce a small number of short, defective RNAs, but the cell's surveillance machinery in the nucleus identifies and disposes of them.

Insco explains, "There are hundreds of steps in making RNAs, and sometimes it doesn't go right. They're mistakes that are usually discarded. In this case, we found that the cell was not cleaning them up. The vacuum cleaner was broken, so the RNAs were building up."

The research findings suggest that targeting CDK13 or the proteins it regulates could offer a promising approach to treating multiple types of cancer. In the case of melanoma alone, a staggering 21% of the examined human tumors showed mutations in CDK13 or downstream proteins.

The team of researchers also discovered mutations in CDK13, ZC3H14, or related proteins in other types of human tumors, including non-melanoma skin cancer, endometrial cancer, colon adenocarcinoma, and small-cell lung cancer.

"There's a cleanup mechanism that isn't working in these cancers," says Zon. "Further defining how RNAs are controlled and processed in cancer will be a major question for developing therapeutics."

This groundbreaking study sheds new light on the intricate molecular mechanisms underlying cancer development. The identification of CDK13 mutations and their impact on the cell's RNA surveillance system opens up exciting possibilities for cancer treatment and we can’t wait to see them unfold. 

 The study was published in the journal Science.

Abstract:

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.