Nucleotide excision repair/TFIIH helicases Rad3 and Ssl2 inhibit short-sequence recombination and Ty1 retrotransposition by similar mechanisms

Eukaryotic genomes contain potentially unstable sequences whose rearrangeme nt threatens genome structure and function. Here we show that certain mutan t alleles of the nucleotide excision repair (NER)/TFIIH helicase genes RAD3 and SSL2 (RAD25) confer synthetic lethality and destabilize the Saccharomy ces cerevisiae genome by increasing both short-sequence recombination and T y1 retrotransposition. The rad3-G595R and ssl1-rtt mutations do not markedl y alter Ty1 RNA or protein levels or target site specificity. However, thes e mutations cause an increase in the physical stability of broken DNA molec ules and unincorporated Ty1 cDNA, which leads to higher levels of short-seq uence recombination and Ty1 retrotransposition. Our results link components of the core NER/TFIIH complex with genome stability, homologous recombinat ion, and host defense against Ty1 retrotransposition via a mechanism that i nvolves DNA degradation.