Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
Department of Toxicogenetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands.
Cell Rep. 2013 Dec 26;5(6):1714-24. doi: 10.1016/j.celrep.2013.11.035. Epub 2013 Dec 19.
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.
高效修复紫外线诱导的 DNA 损伤需要核苷酸切除修复(NER)与许多其他生物过程的精确协调。为了绘制这种串扰图谱,我们在紫外线照射前后对 >45,000 个双突变体进行了定量生长测量,在此基础上生成了一个以差异遗传相互作用为中心的图谱。将遗传数据与物理相互作用网络相结合,确定了在 62 个蛋白质复合物中存在 89 个紫外线诱导的功能相互作用的全局图谱,其中包括 RSC 复合物和几个 NER 因子之间的一些联系。我们表明,RSC 在紫外线损伤后被招募到沉默和转录的基因座,在那里它通过促进核小体重塑来促进有效的修复。最后,对高剂量和低剂量紫外线的反应进行比较表明,遗传重连的程度与紫外线剂量相关,并揭示了一个具有剂量特异性相互作用的网络。本研究提供了大量紫外线诱导相互作用的资源,并说明了一种基于遗传网络定量变化来识别剂量依赖性相互作用的方法。