Complexities of the DNA base excision repair pathway for repair of oxidative DNA damage

Oxidative damage represents the most significant insult to organisms becaus e of continuous production of the reactive oxygen species (ROS) in vivo. Ox idative damage in DNA, a critical target of ROS, is repaired primarily via the base excision repair (BER) pathway which appears to be the simplest amo ng the three excision repair pathways. However, it is now evident that alth ough BER can be carried with four or five enzymes in vitro, a large number of proteins, including some required for nucleotide excision repair (NER), are needed for in vivo repair of oxidative damage. Furthermore, BER in tran scribed vs. nontranscribed DNA regions requires distinct sets of proteins, as in the case of NER. We propose an additional complexity in repair of rep licating vs. nonreplicating DNA. Unlike DNA bulky adducts, the oxidized bas e lesions could be incorporated in the nascent DNA strand, repair of which may share components of the mismatch repair process. Distinct enzyme specif icities are thus warranted for repair of lesions in the parental vs. nascen t DNA strand. Repair synthesis may be carried out by DNA polymerase beta or replicative polymerases delta and epsilon. Thus, multiple subpathways are needed for repairing oxidative DNA damage, and the pathway decision may req uire coordination of the successive steps in repair. Such coordination incl udes transfer of the product of a DNA glycosylase to AP-endonuclease, the n ext enzyme in the pathway. Interactions among proteins in the pathway may a lso reflect such coordination, characterization of which should help elucid ate these subpathways and their in vivo regulation. (C) 2001 Wiley-Liss, In c.