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Small molecule inhibitors of yeast pre-mRNA splicing.
ACS Chem Biol. 2009 Sep 18; 4(9):759-68.AC

Abstract

The spliceosome catalyzes pre-messenger RNA (pre-mRNA) splicing, an essential process in eukaryotic gene expression in which non-protein-coding sequences are removed from pre-mRNA. The spliceosome is a large, molecular complex composed of five small nuclear RNAs (snRNAs) and over 100 proteins. Large-scale rearrangements of the snRNAs and their associated proteins, including changes in base-pairing partners, are required to properly identify the intron-containing pre-mRNA, position it within the spliceosome, and complete the cleavage and ligation reactions of splicing. Despite detailed knowledge of the composition of the spliceosome at various stages of assembly, the critical signals and conformational changes that drive the dynamic rearrangements required for pre-mRNA splicing remain largely unknown. Just as ribosome-binding antibiotics facilitated mechanistic studies of the ribosome, study of the catalytic mechanisms of the spliceosome could be enhanced by the availability of small molecule inhibitors that block spliceosome assembly and splicing at defined stages. We sought to identify inhibitors of Saccharomyces cerevisiae splicing by screening for small molecules that block yeast splicing in vitro. We identified 10 small molecule inhibitors of yeast splicing, including four antibiotics, one kinase inhibitor, and five oxaspiro compounds. We also report that a subset of the oxaspiro derivatives permitted assembly of spliceosomal complexes onto pre-mRNA but blocked splicing prior to the first cleavage reaction.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Aukema KG
Department of Chemistry, University of Northern British Columbia, 3333 University Way, Prince George BC V2N 4Z9, Canada.
Chohan KK
No affiliation info available
Plourde GL
No affiliation info available
Reimer KB
No affiliation info available
Rader SD
No affiliation info available

MeSH

Inhibitory Concentration 50Molecular StructureRNA SplicingRNA, FungalRNA, MessengerSaccharomyces cerevisiaeSmall Molecule LibrariesSpliceosomes

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19634919

Citation

Aukema, Kelly G., et al. "Small Molecule Inhibitors of Yeast pre-mRNA Splicing." ACS Chemical Biology, vol. 4, no. 9, 2009, pp. 759-68.
Aukema KG, Chohan KK, Plourde GL, et al. Small molecule inhibitors of yeast pre-mRNA splicing. ACS Chem Biol. 2009;4(9):759-68.
Aukema, K. G., Chohan, K. K., Plourde, G. L., Reimer, K. B., & Rader, S. D. (2009). Small molecule inhibitors of yeast pre-mRNA splicing. ACS Chemical Biology, 4(9), 759-68. https://doi.org/10.1021/cb900090z
Aukema KG, et al. Small Molecule Inhibitors of Yeast pre-mRNA Splicing. ACS Chem Biol. 2009 Sep 18;4(9):759-68. PubMed PMID: 19634919.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Small molecule inhibitors of yeast pre-mRNA splicing. AU - Aukema,Kelly G, AU - Chohan,Kamalprit K, AU - Plourde,Guy L, AU - Reimer,Kerry B, AU - Rader,Stephen D, PY - 2009/7/29/entrez PY - 2009/7/29/pubmed PY - 2009/11/18/medline SP - 759 EP - 68 JF - ACS chemical biology JO - ACS Chem Biol VL - 4 IS - 9 N2 - The spliceosome catalyzes pre-messenger RNA (pre-mRNA) splicing, an essential process in eukaryotic gene expression in which non-protein-coding sequences are removed from pre-mRNA. The spliceosome is a large, molecular complex composed of five small nuclear RNAs (snRNAs) and over 100 proteins. Large-scale rearrangements of the snRNAs and their associated proteins, including changes in base-pairing partners, are required to properly identify the intron-containing pre-mRNA, position it within the spliceosome, and complete the cleavage and ligation reactions of splicing. Despite detailed knowledge of the composition of the spliceosome at various stages of assembly, the critical signals and conformational changes that drive the dynamic rearrangements required for pre-mRNA splicing remain largely unknown. Just as ribosome-binding antibiotics facilitated mechanistic studies of the ribosome, study of the catalytic mechanisms of the spliceosome could be enhanced by the availability of small molecule inhibitors that block spliceosome assembly and splicing at defined stages. We sought to identify inhibitors of Saccharomyces cerevisiae splicing by screening for small molecules that block yeast splicing in vitro. We identified 10 small molecule inhibitors of yeast splicing, including four antibiotics, one kinase inhibitor, and five oxaspiro compounds. We also report that a subset of the oxaspiro derivatives permitted assembly of spliceosomal complexes onto pre-mRNA but blocked splicing prior to the first cleavage reaction. SN - 1554-8937 UR - https://www.unboundmedicine.com/medline/citation/19634919/Small_molecule_inhibitors_of_yeast_pre_mRNA_splicing_ DB - PRIME DP - Unbound Medicine ER -