Chemical Inhibition of Pre-mRNA Splicing in Living Saccharomyces cerevisiae.

Abstract:

:The spliceosome mediates precursor mRNA splicing in eukaryotes, including the model organism Saccharomyces cerevisiae (yeast). Despite decades of study, no chemical inhibitors of yeast splicing in vivo are available. We have developed a system to efficiently inhibit splicing and block proliferation in living yeast cells using compounds that target the human spliceosome protein SF3B1. Potent inhibition is observed in yeast expressing a chimeric protein containing portions of human SF3B1. However, only a single point mutation in the yeast homolog of SF3B1 is needed for selective inhibition of splicing by pladienolide B, herboxidiene, or meayamycin in liquid culture. Mutations that enable inhibition also improve splicing of branch sites containing mismatches between the intron and small nuclear RNA-suggesting a link between inhibitor sensitivity and usage of weak branch sites in humans. This approach provides powerful new tools for manipulating splicing in live yeast and studies of spliceosome inhibitors.

journal_name

Cell Chem Biol

journal_title

Cell chemical biology

authors

Hansen SR,Nikolai BJ,Spreacker PJ,Carrocci TJ,Hoskins AA

doi

10.1016/j.chembiol.2018.11.008

subject

Has Abstract

pub_date

2019-03-21 00:00:00

pages

443-448.e3

issue

3

eissn

2451-9456

issn

2451-9448

pii

S2451-9456(18)30430-6

journal_volume

26

pub_type

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