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Cell Chem Biol ; 26(3): 443-448.e3, 2019 03 21.
Article in English | MEDLINE | ID: mdl-30639260

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.


Subject(s)
RNA Precursors/metabolism , Ribonucleoprotein, U2 Small Nuclear/genetics , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae/genetics , Small Molecule Libraries/chemistry , Amino Acid Sequence , Epoxy Compounds/chemistry , Epoxy Compounds/pharmacology , Fatty Alcohols/chemistry , Fatty Alcohols/pharmacology , Humans , Macrolides/chemistry , Macrolides/pharmacology , Mutagenesis , Phosphoproteins/chemistry , Phosphoproteins/metabolism , Pyrans/chemistry , Pyrans/pharmacology , RNA Precursors/antagonists & inhibitors , RNA Splicing/drug effects , RNA Splicing Factors/chemistry , RNA Splicing Factors/metabolism , Ribonucleoprotein, U2 Small Nuclear/metabolism , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Sequence Alignment , Small Molecule Libraries/metabolism , Small Molecule Libraries/pharmacology
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