College of Biological Sciences
The expression of over 90% of human genes are affected by alternative splicing (AS) and/or alternative polyadenylation (APA), processes critical for proteome diversity. Despite this importance, the cellular regulatory axis for AS/APA and their biological relevance are not well understood. U2AF (U2 auxiliary factor comprising U2AF1 and U2AF2, for convenience U2AF(1+2)) is an essential splicing factor and forms a constitutive heterodimer. During investigations on mTOR (mammalian target of rapamycin)-regulated pre-mRNA processing, these researchers found that U2AF is, contrary to current consensus, dynamic in association. The researchers identified an mTOR-dependent U2AF2 phosphorylation that facilitates the association of the two U2AF factors. They have also observed that the monomeric U2AF2 and heterodimeric U2AF(1+2) form distinct combinatorial splicing and polyadenylation complexes to coordinate splicing-coupled mRNA truncation by intronic APA. Importantly, a cancer prognostic mutation U2AF1(S34F) resists being dissociated from U2AF2 upon mTOR inhibition. These findings provide mechanistic explanations for long-standing and fundamental questions on U2AF’s plasticity in pre-mRNA processing and introduces a new paradigm in which U2AF1(S34F) antagonizes the U2AF plasticity and disengages transcriptome programing from the regulation of cellular signaling. Moreover, data indicate that this newly discovered mTOR-coordinated U2AF plasticity affects a number of downstream cellular pathways, indicating that mTOR signaling has broader targets than currently appreciated. For example, truncation of PSIP1 (PC4 and SFRS1 Interacting Protein1; a transcriptional coactivator) by mTOR-coordinated U2AF plasticity controls a distinct gene expression program involving replication-dependent histone biogenesis.
Based on these findings, these researchers hypothesize that mTOR signaling-regulated U2AF plasticity is a gateway to combinatorial splicing and intronic APA regulations, and mTOR uses this regulatory axis to control downstream cellular processes, including PSIP1-dependent transcriptome programing. The researchers plan to test this ideas using multidisciplinary approaches to dissect the regulatory mechanism of mTOR-U2AF-PSIP1 truncation and its biological consequence. The aims of the research are:
- Investigate the role of mTOR-U2AF plasticity in transcriptome reprogramming
- Dissect the regulatory axis that connects mTOR, U2AF plasticity, and histone biogenesis
This project will advance the understanding of transcriptome programming by mTOR-coordinated U2AF plasticity and suggest mechanistic cascades that communicate extracellular/cellular environments to gene expression programs. It will also challenge a current model of U2AF1 mutations in cancer pathogenesis. Moreover, this project will establish a link between mTOR and histone biogenesis through U2AF plasticity.