Abstract
The Mediator complex is a transcriptional co-factor for RNA polymerase II (Pol II)-dependent gene expression, with MED19 serving as an integral subunit. While MED19 overexpression has been documented in diverse cancer types to promote tumor progression, the underlying molecular mechanisms remain poorly understood. Here, we uncover a previously unrecognized function whereby MED19 localizes to the nucleolus independently of the Mediator complex. This nucleolar targeting is mediated by a conserved poly-lysine motif at the MED19 C-terminus, which enables binding to ribosomal RNA (rRNA) and fibrillarin (FBL), a catalytic component of the 2'-O-methyltransferase complex and pre-rRNA processing factor. Mechanistically, MED19 facilitates rRNA processing and 2'-O-methylation that promotes the efficiency of internal ribosome entry site-dependent translation for a number of onco-promoting genes including c-Myc. Collectively, these findings reveal a novel Mediator-independent function of MED19 in regulating ribosome-mediated translational control, thus providing mechanistic insights into its onco-promoting role.