Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, Institute for Genetics, University of Cologne, Zülpicher Strasse 47a, 50674 Cologne, Germany.
Nature. 2013 Sep 19;501(7467):416-20. doi: 10.1038/nature12452. Epub 2013 Aug 25.
DNA damage responses have been well characterized with regard to their cell-autonomous checkpoint functions leading to cell cycle arrest, senescence and apoptosis. In contrast, systemic responses to tissue-specific genome instability remain poorly understood. In adult Caenorhabditis elegans worms germ cells undergo mitotic and meiotic cell divisions, whereas somatic tissues are entirely post-mitotic. Consequently, DNA damage checkpoints function specifically in the germ line, whereas somatic tissues in adult C. elegans are highly radio-resistant. Some DNA repair systems such as global-genome nucleotide excision repair (GG-NER) remove lesions specifically in germ cells. Here we investigated how genome instability in germ cells affects somatic tissues in C. elegans. We show that exogenous and endogenous DNA damage in germ cells evokes elevated resistance to heat and oxidative stress. The somatic stress resistance is mediated by the ERK MAP kinase MPK-1 in germ cells that triggers the induction of putative secreted peptides associated with innate immunity. The innate immune response leads to activation of the ubiquitin-proteasome system (UPS) in somatic tissues, which confers enhanced proteostasis and systemic stress resistance. We propose that elevated systemic stress resistance promotes endurance of somatic tissues to allow delay of progeny production when germ cells are genomically compromised.
DNA 损伤反应的细胞自主检查点功能已得到充分研究，这些功能会导致细胞周期停滞、衰老和凋亡。相比之下，针对组织特异性基因组不稳定性的系统反应仍知之甚少。在成年秀丽隐杆线虫中，生殖细胞经历有丝分裂和减数分裂，而体细胞完全是有丝分裂后。因此，DNA 损伤检查点专门在生殖系中起作用，而成年秀丽隐杆线虫的体细胞具有很强的耐辐射性。一些 DNA 修复系统，如全基因组核苷酸切除修复（GG-NER），专门在生殖细胞中去除损伤。在这里，我们研究了生殖细胞中的基因组不稳定性如何影响线虫的体细胞。我们发现生殖细胞中外源和内源性 DNA 损伤会引起对热和氧化应激的抗性升高。这种体细胞应激抗性是由生殖细胞中的 ERK MAP 激酶 MPK-1 介导的，它触发了与先天免疫相关的假定分泌肽的诱导。先天免疫反应导致体细胞中泛素-蛋白酶体系统（UPS）的激活，赋予增强的蛋白质稳定性和全身性应激抗性。我们提出，提高全身性应激抗性可促进体细胞的耐力，以允许在生殖细胞基因组受损时延迟后代的产生。
