Nucleic Acids Research Advance Access published online on July 13, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp572
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LSM1 over-expression in Saccharomyces cerevisiae depletes U6 snRNA levels
1Cancer Biology Graduate Interdisciplinary Program and 2Department of Molecular and Cellular Biology & Howard Hughes Medical Institute, University of Arizona, Tucson, AZ, 85721-0106, USA
*To whom correspondence should be addressed. Tel: +1 520 621 9347; Fax: +1 520 621 4524; Email: rrparker{at}email.arizona.edu
Received May 19, 2009. Revised June 15, 2009. Accepted June 20, 2009.
Lsm1 is a component of the Lsm1-7 complex involved in cytoplasmic mRNA degradation. Lsm1 is over-expressed in multiple tumor types, including over 80% of pancreatic tumors, and increased levels of Lsm1 protein have been shown to induce carcinogenic effects. Therefore, understanding the perturbations in cell process due to increased Lsm1 protein may help to identify possible therapeutics targeting tumors over-expressing Lsm1. Herein, we show that LSM1 over-expression in the yeast Saccharomyces cerevisiae inhibits growth primarily due to U6 snRNA depletion, thereby altering pre-mRNA splicing. The decrease in U6 snRNA levels causes yeast strains over-expressing Lsm1 to be hypersensitive to loss of other proteins required for production or function of the U6 snRNA, supporting a model wherein excess Lsm1 reduces the availability of the Lsm2-7 proteins, which also assemble with Lsm8 to form a complex that binds and stabilizes the U6 snRNA. Yeast strains over-expressing Lsm1 also display minor alterations in mRNA decay and demonstrate increased susceptibility to mutations inhibiting cytoplasmic deadenylation, a process required for both 5'-to-3' and 3'-to-5' pathways of exonucleolytic decay. These results suggest that inhibition of splicing and/or deadenylation may be effective therapies for Lsm1-over-expressing tumors.