Dna Repair
Even though the long-term survival of species may be improved by genetic changes, the survival of individuals requires genetic stability. To achieve this, each living cell has a complement of enzymes whose function is to repair errors or damage in the DNA. Such lesions can arise spontaneously from normal cellular processes, for example errors in replication, or can be generated by external factors such as chemicals or radiation. The altered portion of the DNA is recognized, usually because the DNA becomes distorted, and the damaged bases of sequences removed by nucleases. The correct sequence is then re-synthesized by a polymerase and the ends joined to the original DNA by a ligase. There are a number of enzyme systems which repair DNA damage and nearly all rely on the existence of two copies of the genetic information, one on each strand of the DNA double helix. Thus if the sequence on one strand is accidentally changed, the complementary strand still holds the correct information and can be used as a template to correct the alteration.
Dimerization, or coupling of adjacent pyrimidines within one strand, is one kind of damage caused by ultraviolet light. Pyrimidine cyclobutane dimers form most frequently between two adjacent thymines. Several repair systems can be used to eliminate this kind of photodamage and one example is photoreactivation. The active enzyme in photoreactivation is photolyase which derives energy from near UV light and splits the pyrimidine dimer. Photolyase has been detected in bacteria, fungi, plants and some animals, though not in mammals. Another system frequently utilized by bacteria to repair UV damage is the inducible SOS system. This system is activated when the cell suffers much DNA damage over a short period. SOS repair is induced when DNA replication becomes blocked by a lesion and the system rapidly replaces the lesion by any base. This type of repair is therefore error prone and when the SOS system inserts the wrong base at the site of the lesion, it can create a mutation. The SOS response is often responsible for the numerous mutations occurring following chemical or UV mutagenesis and is only activated as a last resort under extreme conditions, when error free systems of repair can not deal with a large amount of damage.
Other, more complex and precise mechanisms known as excision repair systems are found in all cell types. They include mismatch repair (MMR), base excision repair (BER) and nucleotide excision repair (NER). Occasionally the normal Watson-Crick base pairing between A:T and G:C does not occur correctly and mismatches (e.g. A:A, A:G, C:T etc.) arise. MMR uses a multienzyme system that locates inappropriately matched bases and replaces the incorrect base with a Watson-Crick match. The main problem for MMR is how to recognize which one of a mismatched base-pair is incorrect. If the wrong base, (i.e., the base that is part of the correct DNA sequence, rather than its mismatched partner), is replaced, then a point mutation results. The bacterium Escherichia coli has a special way of identifying which of a mismatched pair is incorrect using chemical modification by methyl (CH3) groups. During replication, only the original template strand is methylated (at a GATC sequence) thus the newly synthesized, unmethylated, strand can be distinguished from it. When the MMR detects a mismatch it will also locate the unmethylated strand at the GATC site. The endonucleases component of the MMR will then only attack and remove all the bases on the unmethylated strand, from the GATC site up to the mismatch. The excised bases are then resynthesized using the old, correct strand as a template.
DNA damage due to the chemical alteration of bases can occur as a result of natural cellular processes, for example the deamination of cytosine to uracil, or as a result of chemical mutagens which modify DNA bases for example, by the addition of methyl (CH 3) or longer alkyl (-H[CH2] n) groups. Such damage is dealt with by the BER system, which uses a battery of enzymes called glycosylases. These catalyse the hydrolytic removal and replacement of an incorrect base with its correct counterpart. The related NER system, found in both bacteria and higher organisms, is able to repair almost any DNA damage that creates large changes in the DNA structure. It involves the cleavage of the DNA backbone on either side of the distortion and the portion of the strand with the lesion is peeled away. The remaining gap is then filled in by DNA polymerase and sealed with DNA ligase.
Other less well characterized repair systems are known to exist and new systems are continually being researched. In humans it is well known that a deficiency in DNA repair is related to a higher incidence of certain kinds of cancer. One well known example is the skin disorder Xeroderma pigmentosum, which makes people prone to UV induced cancers, and is the result of a defect in the NER system.
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