The Ageing Brain: Effects on DNA Repair and DNA Methylation in Mice

Sabine A. S. Langie*, Kerry M. Cameron, Gabriella Ficz, David Oxley, Bartlomiej Tomaszewski, Joanna P. Gorniak, Lou M. Maas, Roger W. L. Godschalk, Frederik J. van Schooten, Wolf Reik, Thomas von Zglinicki, John C. Mathers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Web of Science)

Abstract

Base excision repair (BER) may become less effective with ageing resulting in accumulation of DNA lesions, genome instability and altered gene expression that contribute to age-related degenerative diseases. The brain is particularly vulnerable to the accumulation of DNA lesions; hence, proper functioning of DNA repair mechanisms is important for neuronal survival. Although the mechanism of age-related decline in DNA repair capacity is unknown, growing evidence suggests that epigenetic events (e.g., DNA methylation) contribute to the ageing process and may be functionally important through the regulation of the expression of DNA repair genes. We hypothesize that epigenetic mechanisms are involved in mediating the age-related decline in BER in the brain. Brains from male mice were isolated at 3-32 months of age. Pyrosequencing analyses revealed significantly increased Ogg1 methylation with ageing, which correlated inversely with Ogg1 expression. The reduced Ogg1 expression correlated with enhanced expression of methyl-CpG binding protein 2 and ten-eleven translocation enzyme 2. A significant inverse correlation between Neil1 methylation at CpG-site2 and expression was also observed. BER activity was significantly reduced and associated with increased 8-oxo-7,8-dihydro-2-deoxyguanosine levels. These data indicate that Ogg1 and Neil1 expression can be epigenetically regulated, which may mediate the effects of ageing on DNA repair in the brain.

Original languageEnglish
Article number75
Number of pages19
JournalGenes
Volume8
Issue number2
DOIs
Publication statusPublished - Feb 2017

Keywords

  • DNA methylation
  • epigenetics
  • base excision repair
  • ageing
  • brain
  • gene regulation
  • BASE EXCISION-REPAIR
  • ALZHEIMERS-DISEASE
  • TRANSCRIPTIONAL REGULATION
  • OXIDATIVE STRESS
  • TET ENZYMES
  • EPIGENETIC REGULATION
  • DIETARY RESTRICTION
  • NUCLEAR-DNA
  • MOUSE-BRAIN
  • CANCER

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