Other Free Encyclopedias » Medicine Encyclopedia » Genetics in Medicine - Part 1 » DNA Repair - Sources Of Damage, Base Excision Repair, Nucleotide Excision Repair, Dna Mismatch Repair, Future Directions - Types of DNA Damage

DNA Repair - Nucleotide Excision Repair

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DNA damage that involves particularly "bulky" molecules or chemical bonds between bases, or that significantly distorts the double-stranded structure of DNA, is subject to repair by the nucleotide excision repair (NER) pathway. For example, it has long been known that the ultraviolet (UV) light in sunshine can damage DNA by forming what are called photoproducts. UV radiation excites many types of molecules, causing them to react with each other and with DNA. In particular, UV light can catalyze the formation of chemical bonds between adjacent thymine and/or cytosine bases; these bonds are called intra-strand UV crosslinks (Figure 4A). These crosslinked bases distort the double-stranded structure of DNA and block DNA replication.

A second example of bulky DNA damage is that caused by large, organic molecules like aflatoxin, found in mold-contaminated peanuts, and benzo[ a ]pyrene (Figure 4B), a main component of smoke and soot. Both Figure 4. Two types of mutations repaired by the nucleotide excision repair pathway. Ultraviolet light can trigger a chemical reaction that links adjacent thymines. Complex organic molecules such as benzo[ a ]pyrene can link on to a base such as guanine. aflatoxin and benzo[ a ]pyrene are potent carcinogens. Ingestion or inhalation of these and similar compounds activates the body's detoxification systems, which convert the hydrophobic organic molecules into water-soluble forms for removal. However, the intermediate forms of aflatoxin and benzo[ a ]pyrene produced during the detoxification reaction happen to be very reactive with DNA purines, and form DNA base adducts (they "add on" to DNA). Specifically, such compounds tend to adduct guanine and, to a lesser extent, adenine. These large DNA adducts can cause mutations, and, since they block DNA replication, deletions of large segments of DNA can occur. Also, they activate the cell's damage surveillance systems, and, if not repaired, can cause cell death (apoptosis).

The mechanism of NER, involving some thirty proteins, is more complex than that of BER, but the basic principles are similar: damage recognition, damage excision, DNA repair synthesis, and DNA ligation (Figure 5). Damage recognition is obviously very important (Figure 5, step 1), but how can a single multiprotein complex detect so many different types of DNA damage? The answer is that the DNA damage must (1) distort the normal double-stranded structure of DNA, and/or (2) block transcription by RNA polymerase. Unusual kinks or twists in double-stranded DNA are recognized by the NER damage-recognition multiprotein complex. Also, when RNA polymerase stalls at a damaged DNA base, components of the NER damage-recognition complex are recruited to the site of damage.

Next, the double-stranded DNA adjacent to the damage is unwound by a DNA unwinding enzyme called a helicase (Figure 5, step 2). Unwinding of the DNA allows repair proteins access to the site of damage. The DNA strand containing the damaged base is then cleaved a few nucleotides after the damage, and about twenty-five nucleotides before it, by specific endonucleases associated with the NER protein complex (Figure 5, step 3). Endonucleases are enzymes that cleave inside a segment of DNA.

Next, the DNA segment that contains damage is displaced by DNA polymerase and associated proteins, and a corresponding repair patch is synthesized (Figure 5, step 4). Lastly, DNA ligase seals the nick, joining the newly synthesized piece of DNA to the preexisting strand (Figure 5, step 5).

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