Molecular mechanisms of alternative splicing regulation (360G-Wellcome-209368_Z_17_Z)


<p>Alternative pre-mRNA splicing (AS) is a widespread regulatory mechanism enabling individual genes to generate multiple protein isoforms. We have investigated the mechanisms controlling AS events that are regulated during the transition of smooth muscle cells (SMCs) between contractile and proliferative phenotypes. We have shown how the widely-expressed RNA binding proteins (RBPs) PTBP1 and MBNL1 regulate SMC splicing events. Recently, we identified RBPMS as a potential &ldquo;master&rdquo; regulator of SMC AS. RBPMS is sufficient to switch AS events to the SMC pattern and its activity is strongly modulated by its own AS and by phosphorylation. Critically, RBPMS is sufficient to switch AS to the SMC pattern <em>in vitro</em>. This offers a unique opportunity to determine the molecular anatomy of regulated splicing complexes. We will carry out detailed mechanistic analyses of RBPMS-regulated splicing using a combination of biochemical, proteomic, single-molecule, and structural approaches including Cryo-EM. We will identify critical regulatory interactions between regulatory RBPs and core splicing factors, and test their importance by genome editing and mRNA-Seq. In a complementary aim, we will investigate how peptide-ligand interactions equip PTBP1 to regulate AS and a range of other post-transcriptional processes, and whether a family of such peptide-mediated interactions extends to related RBPs.</p>

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Grant Details

Amount Awarded 1503005
Applicant Surname Smith
Approval Committee Science Interview Panel
Award Date 2017-11-28T00:00:00+00:00
Financial Year 2017/18
Grant Programme: Title Investigator Award in Science
Internal ID 209368/Z/17/Z
Lead Applicant Prof Christopher Smith
Planned Dates: End Date 2023-07-01T00:00:00+00:00
Planned Dates: Start Date 2018-07-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East of England