Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstr. 11, 07745 Jena, Germany.
Nat Rev Mol Cell Biol. 2012 Sep;13(9):579-90. doi: 10.1038/nrm3420.
DNA damage induces cell-intrinsic checkpoints, including p53 and retinoblastoma (RB), as well as upstream regulators (exonuclease 1 (EXO1), ataxia telangiectasia mutated (ATM), ATR, p16(INK4a) and p19(ARF)) and downstream targets (p21, PUMA (p53 upregulated modulator of apoptosis) and sestrins). Clearance of damaged cells by cell-intrinsic checkpoints suppresses carcinogenesis but as a downside may impair stem cell and tissue maintenance during ageing. Modulating the activity of DNA damage checkpoints can either accelerate or decelerate tissue ageing and age-related carcinogenesis. The outcome depends on cell-intrinsic and cell-extrinsic mechanisms that regulate the clearance of damaged cells and on the molecular context in ageing tissues, including the level of DNA damage accumulation itself.
DNA 损伤会诱导细胞内固有检查点，包括 p53 和视网膜母细胞瘤 (RB)，以及上游调节因子 (核酸外切酶 1 (EXO1)、共济失调毛细血管扩张突变 (ATM)、ATR、p16(INK4a) 和 p19(ARF)) 和下游靶标 (p21、PUMA（p53 上调凋亡调节剂）和 sestrins)。细胞内固有检查点清除受损细胞可抑制致癌作用，但不利的一面是可能会在衰老过程中损害干细胞和组织维持。调节 DNA 损伤检查点的活性可以加速或减缓组织衰老和与年龄相关的致癌作用。结果取决于调节受损细胞清除的细胞内和细胞外机制，以及衰老组织中的分子背景，包括 DNA 损伤积累本身的水平。
