DNA damage checkpoints in stem cells, ageing and cancer.
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.
Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstr. 11, 07745 Jena, Germany.
Tobias
T
Sperka
Jianwei
J
Wang
K Lenhard
KL
Rudolph
D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics*; D004249:DNA Damage; D006801:Humans; D008957:Models, Genetic; D013234:Stem Cells / Q000378:metabolism*; D016615:Telomere / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins