Organisms can survive only if their DNA is replicated faithfully and is protected from chemical and physical damage that would change its coding properties. The limits of accurate replication and repair of damage are revealed by the natural mutation rate. Thus, an average nucleotide is likely to be changed by mistake only about once every 10" times it is replicated, although error rates for individual bases can vary over a 10.000-fold range. Much of the accuracy of replication is inherent in the way DNA polymerase copies a template. The initial selection of the correct base is guided by complementary pairing-Accuracy is increased by the proofreading activity of DNA polymerase. Finally, in mismatch repair, the newly synthesized DNA strand is scanned by an enzyme that initiates replacement of DNA containing incorrectly paired bases. Despite these safeguards, mistakes of all types occur: base substitutions, smalt and large additions and deletions, and gross rearrangements of DNA sequences.
Cells have a large repertoire of enzymes devoted to repairing DNA damage that would otherwise be lethal or would alter DNA so as to engender damaging mutations. Some enzymes directly reverse DNA damage, such as pbololyases, which reverse pyrimidine dimer formation. A more versatile Strategy is excision repair, in which a damaged segment is removed and replaced through new DNA synthesis for which the undamaged strand serves as a template. In base excision repair, DNA glycosylases and endonucleases remove only the damaged nucleotide, whereas in nucleotide excision repair a short patch of single-stranded DNA containing the lesion is removed. In E. coli. excision repair is initiated by the L'vrABC endonuclease. which creates a bubble over the site of the damage and cuts oui a 12-nucleotide segment of the DNA strand that includes the lesion. Higher celts carry out nucleotide excision Tepair in a similar manner bul a much larger number of proteins is involved and the excised, single-stranded DNA is 24- to 32-residues long.
An alternative repair method, which is particularly important if no template for repair synthesis is available fas in fhe case of a double-strand break), is recombinations! or double-strand break repair, in which an intact DNA strand is copied from a different hut homologous duplex. Finally, translesion. synthesis enables replication to continue across damage that blocks the progression of a replicating DNA polymerase. Trail s lesion synthesis is mediated by a distincl and widespread family of DNA polymerases thai are able to carry out DNA synthesis in an error-prone manner that does not depend on base pairing.
Mutagenesis and its repair are of concern to us because they permanently affect the genes that organisms inherit and because cancer is often caused by mutations in somatic cells.
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