Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Center for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany.
Nucleic Acids Res. 2018 Jul 6;46(12):6129-6139. doi: 10.1093/nar/gky404.
Ultraviolet (UV) induces distorting lesions to the DNA that can lead to stalling of the RNA polymerase II (RNAP II) and that are removed by transcription-coupled nucleotide excision repair (TC-NER). In humans, mutations in the TC-NER genes CSA and CSB lead to severe postnatal developmental defects in Cockayne syndrome patients. In Caenorhabditis elegans, mutations in the TC-NER genes csa-1 and csb-1, lead to developmental growth arrest upon UV treatment. We conducted a genetic suppressor screen in the nematode to identify mutations that could suppress the developmental defects in csb-1 mutants. We found that mutations in the ERK1/2 MAP kinase mpk-1 alleviate the developmental retardation in TC-NER mutants, while constitutive activation of the RAS-MAPK pathway exacerbates the DNA damage-induced growth arrest. We show that MPK-1 act via insulin/insulin-like signaling pathway and regulates the FOXO transcription factor DAF-16 to mediate the developmental DNA damage response.
紫外线（UV）会导致 DNA 发生扭曲损伤，从而导致 RNA 聚合酶 II（RNAP II）停滞，这些损伤可通过转录偶联核苷酸切除修复（TC-NER）来修复。在人类中，TC-NER 基因 CSA 和 CSB 的突变会导致 Cockayne 综合征患者出生后严重的发育缺陷。在秀丽隐杆线虫中，TC-NER 基因 csa-1 和 csb-1 的突变会导致紫外线处理后发育生长停滞。我们在线虫中进行了遗传抑制筛选，以鉴定能够抑制 csb-1 突变体发育缺陷的突变。我们发现 ERK1/2 MAP 激酶 mpk-1 的突变可以缓解 TC-NER 突变体的发育迟缓，而 RAS-MAPK 途径的组成性激活会加剧 DNA 损伤诱导的生长停滞。我们表明，MPK-1 通过胰岛素/胰岛素样信号通路发挥作用，并调节 FOXO 转录因子 DAF-16 来介导发育相关的 DNA 损伤反应。
