DNA damage response: Selected review and neurologic implications

An estimated 10(5) DNA lesions occur daily in the mammalian genome as a consequence of spontaneous decay, replication errors, and cell metabolism, including reactive oxygen species produced by the mitochondria. Oxidative stress is a major mechanism of DNA damage in the nervous system. Damaged DNA must be repaired to allow the proper reading of the genetic code. The response to DNA damage involves DNA damage recognition first, followed by resection of the affected site, DNA processing, filling the gap by action of DNA polymerases, and sealing of the nick by DNA ligases. Severe DNA damage also triggers chromatin remodeling, transient interruption of the cell cycle, and, if left unrepaired, programmed cell death. Whereas disturbances in DNA repair have been primarily linked to carcinogenesis or immunodeficiency, they can also affect development or survival of cells in the nervous system. A prototype neurologic disorder of DNA repair is ataxia telangiectasia (A-T) due to mutation of the A-T mutated (ATM) gene encoding A-T mutated (ATM), a kinase that coordinates responses to double-strand DNA breaks. Ataxia with oculomotor apraxia (AOA) results from mutations of key proteins involved in DNA end-processing and transcription regulation. Many neurodegenerative disorders are associated with inability to repair oxidative base modifications in both nuclear and mitochondrial DNA. Mismatch and base excision-repair are important modifiers in trinucleotide repeat expansion disorders. There are several reviews on the complex mechanisms involved in DNA repair(1-7) and the neurologic disorders associated with defective DNA repair pathways.(8-16) A comprehensive discussion of these is beyond the scope of this review and only selected topics are discussed here.