Life Sciences & Biotechnology
Title : | Specificity determinants for co-transcriptional degradation of splice-defective pre-mRNAs |
Area of research : | Life Sciences & Biotechnology |
Focus area : | Molecular Biology |
Principal Investigator : | Dr. Venkata RaghavendraAditya Chalamcharla, CSIR- Centre For Cellular And Molecular Biology (CSIR–CCMB), Hyderabad, Telangana |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | cvraditya@ccmb.res.in |
Details
Executive Summary : | The mechanisms of fidelity in pre-mRNA splicing are not fully understood, but several DExD/H ATPases play a crucial role in maintaining splicing fidelity. Recent studies have shown that rejection by ATPases is reversible, necessitating a downstream 'discard pathway' to favor the degradation of rejected splicing intermediates and terminate splicing. The nature of this discard remains enigmatic, and it is unclear whether the composition of defective spliceosomes'marked' for discard is distinct from the ILS complex, which marks the end of a splicing cycle. The 'discard pathway' and the rapid elimination of lariat intermediates can promote spliceosomal cleavage and are essential to generating functional RNA. Preliminary data indicate that the conserved exoribonuclease Xrn2 co-exists with a putative splicing factor Cwf19L1 in a novel dead-end spliceosomal complex that could be involved in the 'discard pathway'. The binding of Cwf19L1 to rejected spliceosomes facilitates the recruitment of Xrn2 for rapid co-transcriptional elimination of the suboptimal precursors and lariat intermediates. Mutations in Cwf19L1 are associated with severe congenital ataxia and developmental delay in humans, but the cellular consequences of its misregulation are unknown. The researchers propose to build on their discoveries to understand how Xrn2 finds its targets for degradation, how the spliceosomal 'discard' pathway can be selectively induced to ensure splicing fidelity, and the cellular consequences of Cwf19L1 misregulation. |
Total Budget (INR): | 72,15,592 |
Organizations involved