Mechanisms of Disease: DNA Repair Defects and Neurological Disease

Kalluri Subba Rao

Disclosures

Nat Clin Pract Neurol. 2007;3(3):162-172. 

In This Article

DNA Damage in Mammalian Cells

DNA, being a chemical consisting of base, deoxyribose and phosphate moieties, is vulnerable to attack by other chemicals, which can result in alterations to its coding properties. Damage to the native structure of DNA can occur through two main mechanisms: spontaneous damage caused by sources within a cell's metabolism, and damage caused by external sources such as chemicals and radiation. Protracted oxidative, hydrolytic, deamination or alkylation reactions within a cell can modify DNA bases, or even sometimes cause a complete loss of bases within DNA, resulting in strand breakage. Similarly, cellular DNA can be damaged by external sources such as ultraviolet or ionizing radiations (X-rays, γ-rays, α particles and cosmic rays), and an array of chemical substances can induce interstrand and intrastrand cross-links, DNA–protein cross-links, bulky DNA adducts, and single-strand and double-strand breaks. This subject has been comprehensively reviewed elsewhere.[1,2] In a metabolically active but nondividing cell such as the neuron, about 50,000 DNA-damaging events can be predicted to occur every day. The type of damage occurring in such a cell is likely to be oxidative in nature, and could result in, for example, base modifications, apurinic or apyrimidinic sites, mismatches caused by deamination, or single-strand breaks. The neuronal cellular machinery is endowed with various DNA repair pathways to counteract such damaging events.

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