Mitchell James R, Hoeijmakers Jan H J, Niedernhofer Laura J
Department of Cell Biology and Genetics, Erasmus University Rotterdam, PO Box 1738, 3000 DR, Rotterdam, The Netherlands.
Curr Opin Cell Biol. 2003 Apr;15(2):232-40. doi: 10.1016/s0955-0674(03)00018-8.
Protection from cancer and ensured longevity are tightly linked in mammals. One of the fundamental mechanisms contributing to both is the cellular response to DNA damage. The appropriate response is an initial attempt at repair, but if the damage is too extensive or compromises DNA metabolism, a signalling cascade triggers cellular senescence or death. Evidence in mice and humans suggests a division of tasks amongst DNA repair pathways: transcription-coupled repair and interstrand crosslink repair of cytotoxic lesions are predominantly responsible for longevity assurance, whereas excision repair of mutagenic lesions provides protection against cancer. Similarly, the signalling component of the DNA-damage response might contribute unequally to organismal outcomes depending on its set point: an inadequate response to DNA damage sanctions carcinogenesis but might limit local ageing, whereas overzealous signalling provides cancer protection but accelerates ageing.
在哺乳动物中，预防癌症和确保长寿紧密相连。促成这两者的一个基本机制是细胞对DNA损伤的反应。适当的反应是最初的修复尝试，但如果损伤过于广泛或损害了DNA代谢，信号级联反应会触发细胞衰老或死亡。小鼠和人类的证据表明，DNA修复途径之间存在任务分工：细胞毒性损伤的转录偶联修复和链间交联修复主要负责确保长寿，而诱变损伤的切除修复则提供抗癌保护。同样，DNA损伤反应的信号成分可能因其设定点而对机体结果产生不平等的影响：对DNA损伤的反应不足会促进致癌作用，但可能会限制局部衰老，而过度活跃的信号传导则提供癌症保护，但会加速衰老。
