Role of nucleotide- and base-excision repair in genotoxin-induced neuronal cell death

G. E. Kisby, H. Lesselroth, A. Olivas, L. Samson, B. Gold, K. Tanaka, M. S. Turker

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Base-excision (BER) and nucleotide-excision (NER) repair play pivotal roles in protecting the genomes of dividing cells from damage by endogenous and exogenous agents (i.e. environmental genotoxins). However, their role in protecting the genome of post-mitotic neuronal cells from genotoxin-induced damage is less clear. The present study examines the role of the BER enzyme 3-alkyladenine DNA glycosylase (AAG) and the NER protein xeroderma pigmentosum group A (XPA) in protecting cerebellar neurons and astrocytes from chloroacetaldehyde (CAA) or the alkylating agent 3-methyllexitropsin (Me-Lex), which produce ethenobases or 3-methyladenine (3-MeA), respectively. Neuronal and astrocyte cell cultures prepared from the cerebellum of wild type (C57BL/6) mice or Aag-/- or Xpa-/- mice were treated with 0.1-50 μM CAA for 24 h to 7 days and examined for cell viability, DNA fragmentation (TUNEL labeling), nuclear changes, and glutathione levels. Aag-/- neurons were more sensitive to the acute (>20 μM) and long-term (>5 μM) effects of CAA than comparably treated wild type neurons and this sensitivity correlated with the extent of DNA fragmentation and nuclear changes. Aag-/- neurons were also sensitive to Me-Lex at comparable concentrations of CAA. In contrast, Xpa-/- neurons were more sensitive than either wild type or Aag-/- neurons to CAA (>10 μM), but less sensitive than Aag-/- neurons to Me-Lex. Astrocytes from the cerebellum of wild type, Aag-/- or Xpa-/- mice were essentially insensitive to CAA at the concentrations tested. These studies demonstrate that BER and NER are required to protect neurons from genotoxin-induced cell death.

Original languageEnglish (US)
Pages (from-to)617-627
Number of pages11
JournalDNA Repair
Volume3
Issue number6
DOIs
StatePublished - Jun 3 2004

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Keywords

  • 3-Methyllexitropsin (Me-Lex)
  • Astrocytes
  • Base-excision repair (BER)
  • Cerebellar neurons
  • Chloroacetaldehyde (CAA)
  • Glutathione (GSH)
  • Nucleotide-excision repair (NER)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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