A Small RNA with a Big Impact on Cell Aging

ABOVE: A small RNA molecule can stall cell division by disrupting the abundance of ribosomes. ©ISTOCK, selvanegra

All cells in the body reach a point where they stop dividing, but some get there quicker under the influence of pressures, such as DNA damage or oxidative stress.¹ Biologists have long studied how proteins hasten cell senescence in response to such signals but they know little about the role that RNAs play.²

Publishing in Cell, scientists zeroed in on an RNA that triggers cells to stop dividing by inhibiting the production of ribosomes.³ Beyond expanding what scientists know about the roles of this class of biomolecules in cell senescence, these findings could inform the design of novel treatments for ribosomal diseases.

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Ribosomes provide cells with the surplus of proteins needed to continue to divide, placing these protein factories as key players in controlling cell senescence. Researchers have shown that small nucleolar RNAs (snoRNAs) modify bases in ribosomal RNAs, but Joshua Mendell, a molecular biologist at the University of Texas Southwestern and study coauthor, wanted to know whether these tweaks can cause ribosomes to ramp down protein production and trigger cell senescence.⁴ 

To test their hypothesis, Mendell and his team leveraged a cell division quirk involving oncogenes. Although oncogenes generally turn healthy cells into rapidly dividing cancers, some mutants can elicit the opposite effect.⁵ The researchers modified human skin cells to express a division-stalling mutant of the Harvey rat sarcoma (Hras) oncogene. To find out whether mutant Hras requires the help of snoRNAs to seize the cell cycle, they shut down the expression of nearly 7,000 snoRNAs one at a time using complementary small guide RNAs. They discovered that a snoRNA called SNORA13 produced one of the most pronounced effects compared to other snoRNA candidates; without it, the mutant oncogene failed to halt cell division.

Further investigation into SNORA13 revealed that it modifies RNA bases in the ribosome’s active site, suggesting that this small RNA may affect the synthesis of all cellular proteins, including ones that stall division. “But what we found is that the chemical modification of the ribosome that is guided by the snoRNA actually had nothing to do with senescence,” Mendell said; the amount of protein synthesis in the cell did not differ between cells with or without SNORA13.  “That was kind of an exciting twist and turn in the story for us,” Mendell noted. 

The researchers went back to the drawing board and emerged with a new hypothesis: Perhaps SNORA13 triggers senescence by altering the abundance of ribosomes. To test this, they isolated and centrifuged the ribosomes to separate their small and large subunits. Mendell and his team found that cells expressing SNORA13 produced fewer of the large subunit than cells lacking the snoRNA, revealing that SNORA13 impedes ribosome synthesis. Although ribosome production slackens, the cell continues to produce essential protein parts that roam freely around the cell. Mendell’s team demonstrated that these mobile proteins bolster tumor protein p53 signaling, which shuts down cell division and switches cells into a senescent state.

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Markus Schosserer, a cell biologist at the Medical University of Vienna who was not involved with the work, noted that the authors used many different methods to validate the pathway from different angles. In future work, he would like to know whether SNORA13 triggers cell senescence in other contexts, such as in response to cell crowding. “Is [SNORA13] also present and required in other cell types?” Schosserer said. “It would be interesting to see what happens if senescence is already established and you then deplete SNORA13,” he posed, suggesting this could reverse cell senescence.

From a clinical standpoint, SNORA13 could draw the interest of researchers hoping to treat ribosomopathies—genetic diseases that lower ribosome abundance.⁶ Mendell said, “Almost all of the factors that we know that are involved in building ribosomes are things that positively regulate ribosomal biogenesis.” This is undesirable because therapeutics that target and obstruct these factors would impede rather than enhance ribosome production. SNORA13 is a rare exception—its inhibition could boost ribosome levels, Mendell suggested. However, he added, “Targeting nucleic acids is really challenging, so there is still a long way to go before that could actually be achieved in the clinic.”