In a screen for mutants that display synthetic lethal interaction with hpr1⌬, a hyperrecombination mutant of Saccharomyces cerevisiae, we have isolated a novel cold-sensitive allele of the acetyl coenzyme A (CoA) carboxylase gene, acc1 cs , encoding the rate-limiting enzyme of fatty acid synthesis. The synthetic lethal phenotype of the acc1 cs hpr1⌬ double mutant was only partially complemented by exogenous fatty acids. hpr1⌬ was also synthetically lethal with a previously isolated, temperature-sensitive allele of ACC1, mtr7 (mRNA transport), indicating that the lethality of the acc1 cs hpr1⌬ double mutant was not allele specific. The basis for the interaction between conditional acc1 alleles and hpr1⌬ was investigated in more detail. In the hpr1⌬ 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 hpr1⌬ 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, hpr1⌬ and acc1 cs mutant cells displayed a defect in nuclear export of polyadenylated RNA. Oversized transcripts were detected in hpr1⌬, and rRNA processing was disturbed, but pre-mRNA splicing appeared wild type. Surprisingly, the transport defect of hpr1⌬ and acc1 cs 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 hpr1⌬ 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.The hpr1⌬ mutant of Saccharomyces cerevisiae was isolated in a screen for mutations that confer an increased mitotic recombination (1, 2). The hpr1⌬ null mutant is temperature sensitive for growth at 37°C and displays a 700-fold-elevated rate of mitotic intrachromatid recombination. Hpr1p has two regions of homology to topoisomerase I, Top1p (3,40), and hpr1⌬ mutants display synthetic lethality with mutations in all three DNA topoisomerase genes, TOP1, TOP2, and TOP3 (3). A fourth synthetic lethal interaction has been found between hpr1⌬ and a mutant carrying a deletion of one copy of the histone H3-H4 genes (10).In hpr1⌬ null mutants, transcription of many physiologically unrelated genes is affected (44) and the temperature-sensitive growth phenotype of hpr1⌬ mutants is suppressed by mutations in components of the general transcription machinery (12, 27, 41). The Hpr1 protein has been found to be in a distinct RNA polymerase II complex (8) and has been suggested to have a functional role in transcription elongation (9).To better understand the in vivo function of Hpr1p, a screen was initiated to isolate additional mutants that exhibit synthetic lethal interaction with hpr1⌬. This screen yielded a novel coldsensitive allele of the acetyl coenzyme A (CoA) carboxylase gene, acc1-200 cs , her...