Département de chimie moléculaire

Ionizing radiation, free radicals, and reactive oxygen species produce hundreds of different DNA lesions. Clustered lesions are typical for ionizing radiation. They compromise the efficiency of the base excision repair (BER) pathway, and as a consequence, they are much more toxic and mutagenic than isolated lesions. Despite their biol. relevance, e.g., in cancer radiotherapy and accidental exposure, they are not very well studied from a structural point of view, and while insights provided by structural studies contribute to the understanding of the repair process, only three NMR (NMR) studies of DNA contg. clusters of lesions were reported. Herein, we report the first NMR soln. structure of two DNAs contg. a bistranded cluster with the 2'-deoxyribonolactone and 8-oxoguanine lesions. Both DNA duplexes feature a 2'-deoxyribonolactone site in the middle of the sequence of one strand and differ by the relative position of the 8-oxoguanine, staggered 3' or 5' side on the complementary strand at a three-nucleotide distance. Depending on its relative position, the repair of the 8-oxoguanine lesion by the base excision repair protein Fpg is either almost complete or inhibited. We found that the structures of the two DNAs contg. a bistranded cluster of two lesions are similar and do not deviate very much from the std. B-form. As no obvious structural deformations were obsd. between the two duplexes, we concluded that the differences in Fpg activity are not due to differences in their global conformation. [on SciFinder(R)]