The Saccharomyces cerevisiae hyperrecombination mutant hpr1 Delta is synthetically lethal with two conditional alleles of the acetyl coenzyme A carboxylase gene and causes a defect in nuclear export of polyadenylated RNA

In a screen for mutants that display synthetic lethal interaction with hpr1 Delta, a hyperrecombination mutant of Saccharomyces cerevisiae, we have is olated a novel cold-sensitive allele of the acetyl coenzyme A (CoA) carboxy lase gene, acc1(cs), encoding the rate-limiting enzyme of fatty acid synthe sis, The synthetic lethal phenotype of the acc1(cs) hpr1 Delta double mutan t was only partially complemented by exogenous fatty acids. hpr1 Delta was also synthetically lethal with a previously isolated, temperature-sensitive allele of ACC1, mtr7 (mRNA transport), indicating that the lethality of th e acc1(cs) hpr1 Delta double mutant was not allele specific. The basis for the interaction between conditional acc1 alleles and hpr1 Delta was investi gated in more detail. In the hpr1 Delta mutant background, acetyl-CoA carbo xylase enzyme activity was reduced about 15-fold and steady-state levels of biotinylated Acc1p and ACC1 mRNA were reduced 2-fold. The reduced Acc1p ac tivity in hpr1 Delta cells, however, did not result in an altered lipid or fatty acid composition of the mutant membranes but rendered cells hypersens itive to soraphen A, an inhibitor of Acc1p, Similar to mtr7, hpr1 Delta and acc1(cs) mutant cells displayed a defect in nuclear export of polyadenylat ed RNA. Oversized transcripts were detected in hpr1 Delta, and rRNA process ing was disturbed, but pre-mRNA splicing appeared wild type, Surprisingly, the transport defect of hpr1 Delta and acc1(cs) mutant cells was accompanie d by an altered ring-shaped structure of the nucleolus. These observations suggest that the basis for the synthetic lethal interaction between hpr1 De lta and acc1 may lie in a functional overlap of the two mutations in nuclea r poly(A)(+) RNA production and export that results in an altered structure of the nucleolus.