Oxidative genome damage and its repair: Implications in aging and neurodegenerative diseases

Muralidhar L. Hegde, Anil K. Mantha, Tapas K. Hazra, Kishor K. Bhakat, Sankar Mitra, Bartosz Szczesny

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

Reactive oxygen species (ROS), generated endogenously during respiration or exogenously by genotoxic agents, induce oxidized bases and single-strand breaks (SSBs) in DNA that are repaired . via the base excision/SSB repair (BER/SSBR) pathway in both the nucleus and mitochondria. Tightly regulated BER/SSBR with multiple sub-pathways is highly complex, and is linked to the replication and transcription. The repair-initiating DNA glycosylases (DGs) or AP-endonuclease (APE1) control the sub-pathway by stably interacting with downstream proteins usually . via their common interacting domain (CID). A nonconserved CID with disordered structure usually located at one of the termini includes the sequences for covalent modifications and/or organelle targeting. While the DGs are individually dispensable, the SSBR-initiating APE1 and polynucleotide kinase 3' phosphatase (PNKP) are essential. BER/SSBR of mammalian nuclear and mitochondrial genomes share the same early enzymes. Accumulation of oxidative damage in nuclear and mitochondrial genomes has been implicated in aging and various neurological disorders. While defects in BER/SSBR proteins have been linked to hereditary neurodegenerative diseases, our recent studies implicated transition metal-induced inhibition of NEIL family DGs in sporadic diseases. This review focuses on the recent advances in repair of oxidatively damages in mammalian genomes and their linkage to aging and neurological disorders.

Original languageEnglish (US)
Pages (from-to)157-168
Number of pages12
JournalMechanisms of Ageing and Development
Volume133
Issue number4
DOIs
StatePublished - Apr 1 2012

Keywords

  • Aging
  • DNA base excision repair
  • DNA glycosylases
  • Neurodegenerative disorders
  • Protein-protein and protein-DNA interactions
  • Reactive oxygen species
  • Single-strand break repair

ASJC Scopus subject areas

  • Aging
  • Developmental Biology

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