DNA damage checkpoints in stem cells, ageing and cancer

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Cycle Checkpoints / genetics*
  • Cell Cycle Proteins / genetics
  • Cell Transformation, Neoplastic / genetics*
  • Cellular Senescence / genetics*
  • DNA Damage*
  • Humans
  • Models, Genetic
  • Stem Cells / metabolism*
  • Telomere / genetics
  • Telomere / metabolism


  • Cell Cycle Proteins