Nuclear PKM2 Promotes Pre-mRNA Processing by Binding G-Quadruplexes

Abstract

Nuclear localization of the pyruvate kinase M2 isoform (PKM2) is widely observed in cancer and correlates with its aggressiveness, but its contribution to gene regulation and pathogenesis remains unclear. We find that PKM2 is a non-canonical RNA binding protein that specifically recognizes folded RNA G-quadruplex (rG4) structures and binds thousands of precursor mRNAs (pre-mRNA) in the nucleus of human cells. Translocation of PKM2 to the nucleus increases expression of pre-mRNAs with rG4s elements within 200 nt of splice sites, likely by promoting mRNA processing through competition with repressive rG4 binding proteins, such as HNRNPF. The same rG4 mRNAs were upregulated in a cancer model undergoing epithelial-to-mesenchymal transition (EMT), highlighting the PKM2-G4 interaction as a potential drug target for EMT-associated tumorigenicity. Our results show a gene-regulatory role for rG4 formation on pre-mRNA and propose that rG4s allow for collective co-transcriptional regulation of related mRNAs by competing RBPs.