UTSW study identifies RNA molecule that regulates cellular aging

Newswise — DALLAS – July 17, 2024 – A team led by UT Southwestern Medical Center researchers has discovered a new way that cells regulate senescence, an irreversible end to cell division. The findings, published in Cell, could one day lead to new interventions for a variety of conditions associated with aging, including neurodegenerative and cardiovascular diseases, diabetes, and cancer, as well as new therapies for a collection of diseases known as ribosomopathies.

“There is great interest in reducing senescence to slow or reverse aging or aging-associated diseases. We discovered a noncoding RNA that when inhibited strongly impairs senescence, suggesting that it could be a therapeutic target for conditions associated with aging,” said Joshua Mendell, M.D., Ph.D., Professor of Molecular Biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He is also a Howard Hughes Medical Institute Investigator.

Dr. Mendell led the study with co-first authors Yujing Cheng, Ph.D., recent graduate of the Genetics, Development, and Disease graduate program, and Siwen Wang, M.D., a former postdoctoral researcher, both in the Mendell Lab.

Cellular senescence is a “double-edged sword,” Dr. Mendell explained. Cells sometimes undergo senescence when a cancer-causing mutation arises, halting uncontrolled cell division and preventing tumors from developing. On the other hand, too much senescence contributes to aging and degenerative diseases.

The Mendell Lab has long studied noncoding RNAs, finding new roles for these molecules in both health and disease. In this newest study, he and his colleagues used a technique for regulating gene activity called CRISPR interference to individually inactivate thousands of noncoding RNAs in human cells that carried a cancer-causing mutation. Usually, this mutation prompts cells to become senescent; however, inactivating a noncoding RNA involved in senescence caused the cells to continue dividing.

These experiments quickly revealed a previously unrecognized regulator of senescence called SNORA13, a member of a family of noncoding RNAs known as small nucleolar RNAs that are thought largely to function as guides for chemical modification of other RNA molecules. A series of additional experiments showed that SNORA13 plays another important and unexpected role: slowing down the construction of ribosomes, cellular machines that synthesize proteins.

Dr. Mendell explained that cellular stress – prompted by a cancer-causing mutation, for example – can perturb ribosome assembly and push cells into senescence. However, removing SNORA13 caused cells to ramp up ribosome assembly, blocking the quality control that would normally trigger senescence and allowing cells to continue dividing.

Learning more about this process could eventually help researchers control it, Dr. Mendell said. For example, developing drugs that push cells into senescence could offer a new way to treat cancer. Conversely, developing drugs that prevent senescence could slow aging and diseases that typically accompany it, such as cardiovascular diseases, neurodegenerative diseases, and diabetes.

In addition, because of SNORA13’s essential function in regulating ribosome assembly, targeting this noncoding RNA could someday be used to treat ribosomopathies, diseases characterized by abnormal ribosome production or function, such as Treacher Collins syndrome or Diamond-Blackfan anemia.

Other UTSW researchers who contributed to this study are Michael Buszczak, Ph.D., Professor of Molecular Biology; Hao Zhu, M.D., Professor in Children’s Medical Center Research Institute at UT Southwestern and of Internal Medicine and Pediatrics and co-leader of the Development and Cancer Research Program in the Simmons Cancer Center; Asha Acharya, Ph.D., and Tsung-Cheng Chang, Ph.D., Assistant Professors of Molecular Biology; Jong-Sun Lee, Ph.D., Assistant Instructor of Molecular Biology; He Zhang, Ph.D., Computational Biologist III; Chunyang Ni, Ph.D., Research Associate; Eric Chen, B.S., graduate student researcher; and Jason Guo, B.S., medical student.

Dr. Mendell holds the Charles Cameron Sprague, M.D. Chair in Medical Science. Dr. Buszczak holds the Lillian B. and Tom B. Rhodes Professorship in Stem Cell Research and is an E.E. and Greer Garson Fogelson Scholar in Medical Research. Dr. Zhu holds the Nancy B. and Jake L. Hamon Distinguished Chair in Therapeutic Oncology Research. Drs. Buszczak and Zhu are also Simmons Cancer Center members. Dr. Zhu is supported by an Emerging Leader Award from the Mark Foundation for Cancer Research.

This study was funded by grants from the Cancer Prevention and Research Institute of Texas (RP220309), The Welch Foundation (I-1961-20210327 and I-1961-20240404), the Mark Foundation for Cancer Research (21-003-ELA), the Department of Defense (W81XWH2110815), and the National Institutes of Health (R01CA282036, R01CA251928, R35GM144043, R01AG079513, and P30 CA142543).

Dr. Mendell is a scientific adviser for Ribometrix Inc. and owns equity in Orbital Therapeutics Inc., both of which are developing RNA-based therapies. Dr. Zhu is academic co-founder of Quotient Therapeutics and Jumble Therapeutics, has sponsored research agreements with Alnylam Pharmaceuticals and Chroma Medicine, and serves on the scientific advisory boards for NewLimit and Ubiquitix. UTSW has filed a provisional patent on the inhibition of SNORA13 as a strategy to increase ribosome biogenesis.

About UT Southwestern Medical Center  

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.