A UV-Induced Genetic Network Links the RSC Complex to Nucleotide Excision Repair and Shows Dose-Dependent Rewiring

Efficient repair of UV-induced DNA damage requires the precise coordination of nucleotide excision repair (NER) with numerous other biological processes. To map this crosstalk, we generated a differential genetic interaction map centered on quantitative growth measurements of >45,000 double mutants before and after different doses of UV radiation. Integration of genetic data with physical interaction networks identified a global map of 89 UV-induced functional interactions among 62 protein complexes, including a number of links between the RSC complex and several NER factors. We show that RSC is recruited to both silenced and transcribed loci following UV damage where it facilitates efficient repair by promoting nucleosome remodeling. Finally, a comparison of the response to high versus low levels of UV shows that the degree of genetic rewiring correlates with dose of UV and reveals a network of dose-specific interactions. This study makes available a large resource of UV-induced interactions, and it illustrates a methodology for identifying dose-dependent interactions based on quantitative shifts in genetic networks. [Display omitted] •Differential genetic analysis of 45,938 mutants was carried out in response to UV•Genetic data link RSC to global genome and transcription-coupled repair•RSC facilitates repair via nucleosome remodeling at sites of UV-induced lesions•High- and low-dose UV induce a set of dose-specific genetic interactions The repair of UV-induced DNA damage requires the coordination of numerous cellular processes. In this study, Van Attikum, Ideker, and colleagues utilize differential epistasis mapping to uncover how the crosstalk between these processes are rewired in response to UV. The data pinpoint a role for the RSC complex in remodeling chromatin at the sites of UV damage to promote efficient repair. This study provides a first draft of the genetic networks governing the response to UV damage.