Lans Hannes, Vermeulen Wim
Department of Genetics, Cancer Genomics Netherlands, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
DNA Repair (Amst). 2015 Aug;32:141-148. doi: 10.1016/j.dnarep.2015.04.025. Epub 2015 May 1.
The various symptoms associated with hereditary defects in the DNA damage response (DDR), which range from developmental and neurological abnormalities and immunodeficiency to tissue-specific cancers and accelerated aging, suggest that DNA damage affects tissues differently. Mechanistic DDR studies are, however, mostly performed in vitro, in unicellular model systems or cultured cells, precluding a clear and comprehensive view of the DNA damage response of multicellular organisms. Studies performed in intact, multicellular animals models suggest that DDR can vary according to the type, proliferation and differentiation status of a cell. The nematode Caenorhabditis elegans has become an important DDR model and appears to be especially well suited to understand in vivo tissue-specific responses to DNA damage as well as the impact of DNA damage on development, reproduction and health of an entire multicellular organism. C. elegans germ cells are highly sensitive to DNA damage induction and respond via classical, evolutionary conserved DDR pathways aimed at efficient and error-free maintenance of the entire genome. Somatic tissues, however, respond differently to DNA damage and prioritize DDR mechanisms that promote growth and function. In this mini-review, we describe tissue-specific differences in DDR mechanisms that have been uncovered utilizing C. elegans as role model.
与DNA损伤反应（DDR）遗传缺陷相关的各种症状，从发育和神经异常、免疫缺陷到组织特异性癌症和加速衰老，表明DNA损伤对不同组织的影响不同。然而，DDR的机制研究大多在体外、单细胞模型系统或培养细胞中进行，这使得难以清晰全面地了解多细胞生物的DNA损伤反应。在完整的多细胞动物模型中进行的研究表明，DDR会因细胞的类型、增殖和分化状态而有所不同。线虫秀丽隐杆线虫已成为重要的DDR模型，似乎特别适合于理解体内组织对DNA损伤的特异性反应，以及DNA损伤对整个多细胞生物的发育、繁殖和健康的影响。秀丽隐杆线虫的生殖细胞对DNA损伤诱导高度敏感，并通过经典的、进化保守的DDR途径做出反应，这些途径旨在高效且无差错地维持整个基因组。然而，体细胞组织对DNA损伤的反应不同，并优先考虑促进生长和功能的DDR机制。在这篇小型综述中，我们描述了以秀丽隐杆线虫为模型揭示的DDR机制中的组织特异性差异。
