Control of Cellular Aging, Tissue Function, and Cancer by p53 Downstream of Telomeres

Cold Spring Harb Perspect Med. 2017 May 1;7(5):a026088. doi: 10.1101/cshperspect.a026088.

Abstract

Telomeres, the nucleoprotein complex at the ends of eukaryotic chromosomes, perform an essential cellular role in part by preventing the chromosomal end from initiating a DNA-damage response. This function of telomeres can be compromised as telomeres erode either as a consequence of cell division in culture or as a normal part of cellular ageing in proliferative tissues. Telomere dysfunction in this context leads to DNA-damage signaling and activation of the tumor-suppressor protein p53, which then can prompt either cellular senescence or apoptosis. By culling cells with dysfunctional telomeres, p53 plays a critical role in protecting tissues against the effects of critically short telomeres. However, as telomere dysfunction worsens, p53 likely exacerbates short telomere-driven tissue failure diseases, including pulmonary fibrosis, aplastic anemia, and liver cirrhosis. In cells lacking p53, unchecked telomere shortening drives chromosomal end-to-end fusions and cycles of chromosome fusion-bridge-breakage. Incipient cancer cells confronting these telomere barriers must disable p53 signaling to avoid senescence and eventually up-regulate telomerase to achieve cellular immortality. The recent findings of highly recurrent activating mutations in the promoter for the telomerase reverse transcriptase (TERT) gene in diverse human cancers, together with the widespread mutations in p53 in cancer, provide support for the idea that circumvention of a telomere-p53 checkpoint is essential for malignant progression in human cancer.

Publication types

  • Review

MeSH terms

  • Animals
  • Apoptosis
  • Cell Cycle Checkpoints
  • Cellular Senescence / genetics*
  • DNA Damage / physiology
  • Humans
  • Mice
  • Mutation
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Signal Transduction*
  • Telomerase / metabolism
  • Telomerase / physiology*
  • Telomere / genetics*
  • Telomere / physiology
  • Telomere Shortening
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / physiology*
  • Up-Regulation

Substances

  • Tumor Suppressor Protein p53
  • Telomerase