Enzyinology of huinan nucleotide excision repair

Abstract Damaged bases are eliminated from human genomes by two completely different excision mechanisms: repair by base excision and repair by nucleotide excision. Base excision involves the hydrolysis of N-glycosidic bonds and is restricted to a rather narrow range of defective or inappropriate DNA constituents (1, 2). Nucleotide excision repair (NER), on the other hand, proceeds through dual endonucleolytic cleavage of damaged strands and is capable of removing a nearly infinite variety of base lesions with little regard for the modification itself. The extraordinary substrate versatility of NER is necessary to cope with bulky (helix distorting) injuries to DNA that arise mainly from exposure to UV radiation and chemical carcinogens (3-6). NER is, in fact, the sole mechanism for the error-free removal of bulky DNA adducts in human cells and, as a consequence, provides a key line of defence against such genotoxic adversities. In addition, NER displays a backup role for the repair of apurinic-apyrimidinic (AP) sites, thymine glycol, 8-hydroxyguanine, O6-methylguanine, and similar non-bulky base lesions that are normally processed by more specific repair enzymes, primarily AP endonucleases, DNA glycosylases, or O6- methylguanine-DNA methyltransferase (7, 8). To exert these multiple DNA repair functions, human NER lacks selectivity for a particular type of damage, i.e. a limited number of gene products accommodates and processes a large repertoire of unrelated base modifications while ignoring the normal conformational fluctuations of undamaged DNA. This flexibility is achieved by means of a repair strategy that avoids the direct processing of modified deoxyribonucleotide residues, but, instead, operates exclusively on unmodified segments of native DNA around each lesion site.