Quantitative prediction of variant effects on alternative splicing in MAPT using endogenous pre-messenger RNA structure probing.

ABSTRACT: Splicing is highly regulated and is modulated by numerous factors. Quantitative predictions for how a mutation will affect precursor mRNA (pre-mRNA) structure and downstream function are particularly challenging. Here, we use a novel chemical probing strategy to visualize endogenous precursor and mature MAPT mRNA structures in cells. We used these data to estimate Boltzmann suboptimal structural ensembles, which were then analyzed to predict consequences of mutations on pre-mRNA structure. Further analysis of recent cryo-EM structures of the spliceosome at different stages of the splicing cycle revealed that the footprint of the B^act complex with pre-mRNA best predicted alternative splicing outcomes for exon 10 inclusion of the alternatively spliced MAPT gene, achi

SUBMITTER: Kumar J 

PROVIDER: S-EPMC9236610 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature