Cancer-Related Mutations Alter RNA-Driven Functional Cross-Talk Underlying Premature-Messenger RNA Recognition by Splicing Factor SF3b

The pillar of faithful premature-messenger (pre-mRNA)splicingis the precise recognition of key intronic sequences by specific splicingfactors. The heptameric splicing factor 3b (SF3b) recognizes the branchpoint sequence (BPS), a key part of the 3 & PRIME; splice site. SF3bcontains SF3B1, a protein holding recurrent cancer-associated mutations.Among these, K700E, the most-frequent SF3B1 mutation, triggers aberrantsplicing, being primarily implicated in hematologic malignancies.Yet, K700E and the BPS recognition site are 60 & ANGS; apart, suggestingthe existence of an allosteric cross-talk between the two distal spots.Here, we couple molecular dynamics simulations and dynamical networktheory analysis to unlock the molecular terms underpinning the impactof SF3b splicing factor mutations on pre-mRNA selection. We establishthat by weakening and remodeling interactions of pre-mRNA with SF3b,K700E scrambles RNA-mediated allosteric cross-talk between the BPSand the mutation site. We propose that the altered allostery contributesto cancer-associated missplicing by mutated SF3B1. This finding broadensour comprehension of the elaborate mechanisms underlying pre-mRNAmetabolism in eukaryotes.

Automated summary

The key to accurate pre-mRNA splicing is the recognition of intronic sequences by specific splicing factors. The splicing factor 3b (SF3b) recognizes the branchpoint sequence (BPS), which is crucial for splice site selection. Mutations in SF3B1, including the most common K700E mutation, lead to aberrant splicing and are associated with hematologic malignancies. This study combines molecular dynamics simulations and dynamical network theory analysis to understand how SF3B mutations affect pre-mRNA selection. The findings suggest that the mutated SF3B1 disrupts RNA-mediated allosteric cross-talk between the BPS and the mutation site, contributing to cancer-associated missplicing. This study enhances our understanding of pre-mRNA metabolism in eukaryotes.