Oxidation in the nucleotide pool, the DNA damage response and cellular senescence: Defective bricks build a defective house

Research output: Contribution to journalReview article

33 Scopus citations

Abstract

Activation of persistent DNA damage response (DDR) signaling is associated with the induction of a permanent proliferative arrest known as cellular senescence, a phenomenon intrinsically linked to both tissue aging as well as tumor suppression. The DNA damage observed in senescent cells has been attributed to elevated levels of reactive oxygen species (ROS), failing DNA damage repair processes, and/or oncogenic activation. It is not clear how labile molecules such as ROS are able to damage chromatin-bound DNA to a sufficient extent to invoke persistent DNA damage and DDR signaling. Recent evidence suggests that the nucleotide pool is a significant target for oxidants and that oxidized nucleotides, once incorporated into genomic DNA, can lead to the induction of a DNA strand break-associated DDR that triggers senescence in normal cells and in cells sustaining oncogene activation. Evasion of this DDR and resulting senescence is a key step in tumor progression. This review will explore the role of oxidation in the nucleotide pool as a major effector of oxidative stress-induced genotoxic damage and DDR in the context of cellular senescence and tumorigenic transformation.

Original languageEnglish (US)
Pages (from-to)71-81
Number of pages11
JournalMutation Research - Genetic Toxicology and Environmental Mutagenesis
Volume703
Issue number1
DOIs
StatePublished - Nov 28 2010

Keywords

  • 8-Oxo-dGTP
  • 8-Oxoguanine
  • Cellular senescence
  • DNA strand breaks
  • Non-small cell lung carcinoma
  • Ras oncogene
  • ROS

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Genetics

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