An age-related increase in resistance to DNA damage-induced apoptotic cell death is associated with development of DNA repair mechanisms

Alejandro A. Romero, Stephane R. Gross, Ke-Yi Cheng, Noriko K. Goldsmith, Herbert M. Geller

Research output: Contribution to journalArticle

Abstract

Neurons in the developing brain die via apoptosis after DNA damage, while neurons in the adult brain are generally resistant to these insults. The basis for this resistance is a matter of conjecture. We report here that cerebellar granule neurons (CGNs) in culture lose their competence to die in response to DNA damage as a function of time in culture. CGNs at either 1 day in vitro (DIV) or 7 DIV were treated with the DNA damaging agents camptothecin, UV or gamma-irradiation and neuronal survival measured. The younger neurons were effectively killed by these agents, while the older neurons displayed a significant resistance to killing. Neuronal survival did not change with time in culture when cells were treated with C2-ceramide or staurosporine, agents which do not target DNA. The resistance to UV irradiation developed over time in culture and was not due to changes in mitotic rate. Increases in DNA strand breakage, up-regulation of the levels of both p53 and its phosphorylated form and nuclear translocation of p53 were equivalent in both older and younger neurons, indicating a comparable p53 stress response. In addition, we show that treatment of older neurons with pharmacological inhibitors of distinct components of the DNA repair machinery promotes the accumulation of DNA damage and sensitizes these cells to the toxic effects of UV exposure. These data demonstrate that older neurons appear to be more proficient in DNA repair in comparison to their younger counterparts, and that this leads to increased survival after DNA damage.
Original languageEnglish
Pages (from-to)1275-1287
Number of pages13
JournalJournal of Neurochemistry
Volume84
Issue number6
DOIs
Publication statusPublished - Mar 2003

Fingerprint

Cell death
DNA Repair
DNA Damage
Neurons
Repair
Cell Death
DNA
Brain
Irradiation
Camptothecin
Staurosporine
Poisons
Cell culture
Mental Competency
Machinery
Up-Regulation
Cell Culture Techniques
Pharmacology
Apoptosis

Keywords

  • granule neuron
  • ionizing irradiation

Cite this

Romero, Alejandro A. ; Gross, Stephane R. ; Cheng, Ke-Yi ; Goldsmith, Noriko K. ; Geller, Herbert M. / An age-related increase in resistance to DNA damage-induced apoptotic cell death is associated with development of DNA repair mechanisms. In: Journal of Neurochemistry. 2003 ; Vol. 84, No. 6. pp. 1275-1287.
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An age-related increase in resistance to DNA damage-induced apoptotic cell death is associated with development of DNA repair mechanisms. / Romero, Alejandro A.; Gross, Stephane R.; Cheng, Ke-Yi; Goldsmith, Noriko K.; Geller, Herbert M.

In: Journal of Neurochemistry, Vol. 84, No. 6, 03.2003, p. 1275-1287.

Research output: Contribution to journalArticle

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