DNA Repair

Published on 15/03/2015 by admin

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Chapter 34 DNA Repair

Daniel B. Yarosh, Kenneth A. Smiles

INTRODUCTION

DNA is the central operator of skin cells. Accumulating evidence suggests that damage to DNA is a major cause of the acute effects of sun exposure, as well as the chronic conditions of aging and photoaging. While our natural repair system offers significant protection, new ingredients entering the cosmeceutical market offer the promise of enhancing DNA repair. This chapter will examine the methods and evidence to support these claims.

SOURCES OF DNA DAMAGE

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

• Intrinsic metabolism

During aerobic energy generation about 2% of all the oxygen burned ends up as reactive oxygen species (ROS). These damage DNA most frequently by oxidizing the guanine base to form 8-oxo-guanine (8oGua), which is often misread by the DNA replication machinery causing a change in the sequence of the progeny strands, resulting in mutations. This is particularly serious for mitochondrial DNA, which is closest to the source of the short-lived ROS. An unfolding area of research is the role of mitochondrial DNA in chronic diseases of aging.

• 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.

DNA REPAIR

Because DNA damage is continual, DNA repair systems are found in all organisms to reverse or remove these altered bases. Many plants and animals (but not humans) have an enzyme called photolyase that is able to absorb visible light and use the energy to directly split apart the fused bases in a CPD or 6–4 photoproduct, restoring the native DNA sequence. Humans rely on a complex of DNA repair enzymes that recognize distortions in the DNA, such as those caused by CPD or 8oGua, and remove them by cutting out the single strand of DNA. Special enzymes called endonucleases (e.g. T4 endonuclease V, UV endonuclease) specifically target only CPD and the OGG1 glycosylase binds only to 8oGua. Once the damaged bases have been removed, the gap in the DNA is restored by adding in undamaged bases, using the opposite strand as a template.

O⁶meGua in DNA is repaired in a surprising way by the DNA repair enzyme alkylguanine transferase (AGT) that actually removes the alkyl group from DNA and transfers it to a cysteine residue of the enzyme, without removing any bases from DNA.

MEASURING DNA REPAIR

DNA repair is a multistep process and no one assay measures all aspects of it. More importantly, erroneous conclusions are sometimes drawn from using the wrong assay to measure repair.

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