DNA Repair

Published on 15/03/2015 by admin

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Last modified 15/03/2015

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Chapter 34 DNA Repair

SOURCES OF DNA DAMAGE

DNA damage comes from two sources: the intrinsic metabolism of the cell and environmental insult.

• Environmental insult

By far the most serious damage to skin DNA is from the sun. Solar ultraviolet radiation (UV) also causes the formation of ROS which result in 8oGua. In mitochondria, repeated doses of UVA result in the accumulation of a characteristic deletion mutation in mitochondrial DNA. The frequency of this characteristic mutation in human skin increases with sun exposure, suggesting that it is an internal dosimeter for cumulative sun exposure. But 10-times more frequent than 8oGua is the cyclobutane pyrimidine dimer (CPD), which is DNA damage caused by direct absorption of UV photons without any ROS intermediate. UV causes two adjacent DNA bases to fuse together in a cyclobutane ring, in a photochemical reaction that takes about 15 picoseconds; antioxidants cannot stop it because no free radicals are involved. A second type of base fusion, called a 6–4 photoproduct, is similarly formed about one-sixth as frequently as CPD. Because these fused bases distort the DNA much more than 8oGua, they are much more mutagenic than 8oGua, and consequently much more carcinogenic. CPD causes a characteristic type of DNA mutation, and these signature mutations are frequently found in key cancer genes in squamous and basal cell carcinomas. This is the smoking gun that connects CPDs to skin cancer.

Alkylation is a third type of DNA damage in which an alkyl group is added to DNA. The most prevalent additions are at the 7 position of guanine (N7meGua) and to the phosphates of the DNA backbone, but a much less common form of damage—alkylation of the 6 position of guanine (O6meGua)—is the most mutagenic and hence the most dangerous. This type of damage is usually caused by toxins, such as from some of the chemicals in cigarette smoke, and by drugs. The premature signs of aging in the skin induced by cigarette smoking may be associated with the alkylation damage from alkylating agents in cigarette smoke transported through the circulation to the skin. Additionally, exposure to other chemicals via exposure to industrial pollution and drugs with DNA alkylating potential may have some role in what has been considered normal skin aging.