Insco has further shown that the protein CDK13 is central to the cellular RNA surveillance/cleanup system. It modifies a protein called ZC3H14 and recruits the protein complex to do its cleanup work. She found that CDK13 functions similarly in zebrafish, mouse, and human cells.
Overall, this study suggests that CDK13, or the proteins it regulates, may be targeted to treat multiple cancers.
In melanoma alone, 21% of the human tumors the team looked at had mutations. CDK13 or one of its downstream proteins.
The team also found mutations CDK13, ZC3H14or associated proteins in other human tumors, including non-melanoma skin cancer, endometrial cancer, colon adenocarcinoma, and small cell lung cancer.
“There are cleanup mechanisms that don’t work in these cancers,” Zon said. “Further defining how RNA is regulated and processed in cancer will be a major issue for developing therapeutics.”
Authorship, Funding and Disclosure
Additional authors are Brian Abraham, Sara Dubbury, Ines Kaltheuner, Sofia Dust, Constance Wu, Kevin Chen, David Liu, Stanislav Bellaousov, Anna Cox, and Benjamin Martin. Tongwu Zhang, Calvin Ludwig, Tania Fabo, Rodsy Modhurima, Dakarai Esgdaille, Telmo Henriques, Kevin Brown, Stephen Chanock, Matthias Geyer, Karen Adelman, Phillip Sharp, Richard Young and Paul Bouts.
This study was supported by the Damon Runyon Cancer Foundation, American Society of Clinical Oncology, National Institutes of Health (Grants T32HL116324, T32GM135134, R35GM144283, P01CA042063, R01GM034277, R01CA133404, R01CA103846, R01GM141544, K08). was funded by CA248727, and grants from the Institutional Research Program (IRP) Division of Cancer Epidemiology and Genetics), Charles S. Memorial Sloan Kettering Starr Foundation Cancer Consortium, Hope Funds for Cancer Research Grilo-Marxuach Family Fellowship, American Lebanese Syrian Associated Charities, University of Rochester Health Sciences Center, the David H. Koch Foundation, the Ludwig Center at Harvard, and the German Research Foundation under the German Excellence Strategy (EXC2151–390873048 and grant GE 976/9-2).
Young is the founder and shareholder of Syros Pharmaceuticals, CAMP4 Therapeutics, Omega Therapeutics, and Dewpoint Therapeutics. Sharp is a shareholder of Syros Pharmaceuticals. Zon is the founder and shareholder of Fate Therapeutics, CAMP4 Therapeutics, Scholar Rock, and a consultant to Celularity. Abraham is a shareholder of Syros Pharmaceuticals. Adelman is a consultant at Syros Pharmaceuticals and serves on the Scientific Advisory Board of CAMP4 Therapeutics. Boutz is a paid scientific consultant for Skyhawk Therapeutics, Inc. Zon and Insco filed Patent Application No. July 21, 2022 by Children’s Medical Center Corporation in his PCT/US2022/037839 entitled “Selective Nuclear RNA Degradation as a Therapeutic Mechanism.” The remaining authors declare no competing interests.
Adapted from Boston Children news release.