Recent studies expanded our knowledge of diverse pro-survival functions of short non-coding vault RNAs. One of the human vault RNA paralogs, vtRNA1-1, modulates several intracellular processes, including proliferation, apoptosis, autophagy, and drug resistance in various types of human cancer cells. However, protein interaction partners and mechanisms by which vtRNA1-1 levels are controlled within the cells remained elusive. Here, we describe a regulatory process for vtRNA1-1 stabilization mediated by the newly identified interacting proteins, TRIM21 and TRIM25, in human hepatocellular carcinoma (HCC) cells. Depleting TRIM21 or TRIM25 reduced the stability of vtRNA1-1 both in vivo and in vitro. We also identified the responsible sequence of vtRNA1-1 for the stability regulation by TRIM21 and TRIM25 and revealed another critical factor for vtRNA1-1 stability, an NSUN2-mediated methylation at C69 of vtRNA1-1. Consequently, our findings demonstrated that the TRIM proteins govern the stability of vtRNA1-1 depending on its methylation status in HCC cells. Since vtRNA1-1 is crucial for pro-survival characteristics in HCC cells, insight into vtRNA1-1 protein binding partners and the regulation of its stability can impact the development of new anticancer strategies.
Copyright: © 2025 Kong, Polacek. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.