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Gene Expression

The Saccharomyces cerevisiae Hyperrecombination Mutant hpr1Δ Is Synthetically Lethal with Two Conditional Alleles of the Acetyl Coenzyme A Carboxylase Gene and Causes a Defect in Nuclear Export of Polyadenylated RNA

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Pages 3415-3422 | Received 20 Aug 1998, Accepted 12 Feb 1999, Published online: 28 Mar 2023
 

Abstract

In a screen for mutants that display synthetic lethal interaction with hpr1Δ, a hyperrecombination mutant of Saccharomyces cerevisiae, we have isolated a novel cold-sensitive allele of the acetyl coenzyme A (CoA) carboxylase gene,acc1cs, encoding the rate-limiting enzyme of fatty acid synthesis. The synthetic lethal phenotype of the acc1cs hpr1Δ double mutant was only partially complemented by exogenous fatty acids. hpr1Δ was also synthetically lethal with a previously isolated, temperature-sensitive allele of ACC1, mtr7 (mRNA transport), indicating that the lethality of the acc1cshpr1Δ double mutant was not allele specific. The basis for the interaction between conditional acc1 alleles and hpr1Δ was investigated in more detail. In the hpr1Δ mutant background, acetyl-CoA carboxylase enzyme activity was reduced about 15-fold and steady-state levels of biotinylated Acc1p and ACC1 mRNA were reduced 2-fold. The reduced Acc1p activity in hpr1Δ cells, however, did not result in an altered lipid or fatty acid composition of the mutant membranes but rendered cells hypersensitive to soraphen A, an inhibitor of Acc1p. Similar to mtr7, hpr1Δ and acc1cs mutant cells displayed a defect in nuclear export of polyadenylated RNA. Oversized transcripts were detected in hpr1Δ, and rRNA processing was disturbed, but pre-mRNA splicing appeared wild type. Surprisingly, the transport defect of hpr1Δ and acc1cs mutant cells was accompanied by an altered ring-shaped structure of the nucleolus. These observations suggest that the basis for the synthetic lethal interaction between hpr1Δ and acc1 may lie in a functional overlap of the two mutations in nuclear poly(A)+ RNA production and export that results in an altered structure of the nucleolus.

ACKNOWLEDGMENTS

We thank S. A. Henry and R. Rothstein for strains, A. Hinnen for the gift of soraphen A, J. P. Aris for the anti-Nop1p antibody, and A. Leber for critically reading the manuscript.

This work was supported by the Swiss National Science Foundation (823A-046702 to R.S.), the Fonds zur Förderung der wissenschaftlichen Forschung in Österreich (project 11731 to S.D.K.), and the National Institutes of Health (grant GM30439 to H.L.K.).

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