Transcriptional profiling of the age-related response to genotoxic stress points to differential DNA damage response with age

Kirk Simon, Anju Mukundan, Samantha Dewundara, Holly Van Remmen, Alan A. Dombkowski, Diane C. Cabelof

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

The p53 DNA damage response attenuated with age and we have evaluated downstream factors in the DNA damage response. In old animals p21 protein accumulates in the whole cell fraction but significantly declines in the nucleus, which may alter cell cycle and apoptotic programs in response to DNA damage. We evaluated the transcriptional response to DNA damage in young and old and find 2692 genes are differentially regulated in old compared to young in response to oxidative stress (p < 0.005). As anticipated, the transcriptional profile of young mice is consistent with DNA damage induced cell cycle arrest while the profile of old mice is consistent with cell cycle progression in the presence of DNA damage, suggesting the potential for catastrophic accumulation of DNA damage at the replication fork. Unique sets of DNA repair genes are induced in response to damage in old and young, suggesting the types of damage accumulating differs between young and old. The DNA repair genes upregulated in old animals point to accumulation of replication-dependent DNA double strand breaks (DSB). Expression data is consistent with loss of apoptosis following DNA damage in old animals. These data suggest DNA damage responses differ greatly in young and old animals.

Original languageEnglish (US)
Pages (from-to)637-647
Number of pages11
JournalMechanisms of Ageing and Development
Volume130
Issue number9
DOIs
StatePublished - Sep 1 2009

Keywords

  • Aging
  • Cell cycle
  • DNA damage response
  • DNA repair
  • p53

ASJC Scopus subject areas

  • Aging
  • Developmental Biology

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