Repair of Endogenous DNA Damage

The remarkable stability of genes seemed a puzzlingfeature in the early days of molecular biology. It was evensuggested that new laws of physics might emerge to explain biological paradigms such as the resilience of thegenetic information. The complementary sequences inthe DNA double-helical structure provided a partial answer as to how this stability is retained, but it still tookmore than 10 years after the Watson and Crick 1953model to realize that radiation-damaged residues in DNAcould be corrected by a local excision-repair process. Inretrospect, the early concerns were fully justified; mammalian cellular DNA is a constant target of thermal"noise" in the form of spontaneous hydrolysis at 37ºC,and it is also susceptible to damage caused by active oxygen as well as reactive metabolites and coenzymes. Theresulting lesions are generally removed by the base excision repair (BER) pathway, resulting in short replacementpatches within one of the two DNA strands. Consequently, nonreplicating DNA is not absolutely stable butturns over at a relevant, albeit slow, rate in vivo. This endogenous repair is sufficiently accurate and efficient toexplain the apparent stability of the genetic material...