LMO7-mediated POLR2A degradation promotes cellular senescence through the MDM4/p53/p21 axis.

As the largest subunit of RNA polymerase II, POLR2A plays an irreplaceable role in gene expression, with the regulation of its own expression and physiological function having attracted widespread attention. Here we report POLR2A as a critical guardian against cellular senescence. A significant decline in POLR2A expression was observed in senescent cells and certain tissues of aging mice. Whereas its depletion dramatically induced cellular senescence, conversely, activating endogenous POLR2A expression in senescent cells using CRISPRa technology alleviated the senescent phenotype. We further demonstrated that POLR2A-induced senescence is p53-dependent, as evidenced by the activation of the p53/p21 pathway upon POLR2A knockdown and the rescue of the senescence phenotype following co-depletion of POLR2A and p53. Bioinformatic analysis on RNA-seq data from POLR2A depletion and replicative senescent cells led to the identification of MDM4 as the key mediator of p53 upregulation following POLR2A knockdown. Most intriguingly, immunoprecipitation assay further revealed that the E3 ligase LMO7 was recruited to POLR2A to promote the ubiquitination and proteasomal degradation of POLR2A under cellular senescence. Depletion of LMO7 abolished the ubiquitination and reduction of POLR2A in H₂O₂-induced senescent cells. Taken together, we concluded that the LMO7-induced POLR2A degradation drived cellular senescence through the MDM4/p53/p21 axis.