DNA repair in neurons: So if they don't divide what's to repair?

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Mutat Res. 2006 Jul 29

DNA repair in neurons: So if they don't divide what's to repair?

Fishel ML, Vasko MR, Kelley MR.

Department of Pediatrics (Section of Hematology/Oncology), Herman B

Wells Center for Pediatric Research, Indiana University School of

Medicine, 1044 W. Walnut, Room 302C, Indianapolis, IN 46202, United

States.

Neuronal DNA repair remains one of the most exciting areas for

investigation, particularly as a means to compare the DNA repair

response in mitotic (cancer) vs. post-mitotic (neuronal) cells. In

addition, the role of DNA repair in neuronal cell survival and

response to aging and environmental insults is of particular

interest.

DNA damage caused by reactive oxygen species (ROS) such as generated

by mitochondrial respiration includes altered bases, abasic sites,

and single- and double-strand breaks which can be prevented by the

DNA base excision repair (BER) pathway. Oxidative stress accumulates

in the DNA of the human brain over time especially in the

mitochondrial DNA (mtDNA) and is proposed to play a critical role in

aging and in the pathogenesis of several neurological disorders

including Parkinson's disease, ALS, and Alzheimer's diseases.

Because DNA damage accumulates in the mtDNA more than nuclear DNA,

there is increased interest in DNA repair pathways and the

consequence of DNA damage in the mitochondria of neurons. The type of

damage that is most likely to occur in neuronal cells is oxidative

DNA damage which is primarily removed by the BER pathway. Following

the notion that the bulk of neuronal DNA damage is acquired by

oxidative DNA damage and ROS, the BER pathway is a likely area of

focus for neuronal studies of DNA repair. BER variations in brain

aging and pathology in various brain regions and tissues are

presented. Therefore, the BER pathway is discussed in greater detail

in this review than other repair pathways.

Other repair pathways including direct reversal, nucleotide excision

repair (NER), mismatch repair (MMR), homologous recombination and non-

homologous end joining are also discussed.

Finally, there is a growing interest in the role that DNA repair

pathways play in the clinical arena as they relate to the

neurotoxicity and neuropathy associated with cancer treatments. Among

the numerous side effects of cancer treatments, major clinical

effects include neurocognitive dysfunction and peripheral neuropathy.

These symptoms occur frequently and have not been effectively studied

at the cellular or molecular level. Studies of DNA repair may help

our understanding of how those cells that are not dividing could

succumb to neurotoxicity with the clinical manifestations discussed

in the following article.