High-copy-number expression of Sub2p, a member of the RNA helicase superfamily, suppresses hpr1-mediated genomic instability

We report on a novel role for a pre-mRNA splicing component in genome stabi lity. The Hpr1 protein, a component of an RNA polymerase II complex and req uired for transcription elongation, is also required for genome stability. Deletion of HPR1 results in a 1,000-fold increase in genome instability, de tected as direct-repeat instability. This instability can be suppressed by the high-copy-number SUB2 gene, which is the Saccharomyces cerevisiae homol ogue of the human splicing factor hUAP56. Although SUB2 is essential, condi tional alleles grown at the permissive temperature complement the essential function of SUB2 yet reveal nonessential phenotypes. These studies have un covered a role for SUB2 in preventing genome instability. The genomic insta bility observed in sub2 mutants can be suppressed by high-copy-number HPR1. A deletion mutant of CDC73, a component of a PolII complex, is also unstab le for direct repeats. This too is suppressed by high-copy-number SUB2. Thu s, defects in both the transcriptional machinery and the pre-mRNA splicing machinery can be sources of genome instability. The ability of a pre-mRNA s plicing factor to suppress the hyperrecombination phenotype of a defective PolII complex raises the possibility of integrating transcription, RNA proc essing, and genome stability or a second role for SUB2.