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

Abstract

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.