Oxidative DNA damage processing and changes with aging

Living organisms are constantly exposed to oxidative stress from environmen tal agents and from endogenous metabolic processes. The resulting oxidative modifications occur in proteins, lipids and DNA. Since proteins and lipids are readily degraded and resynthesized, the most significant consequence o f the oxidative stress is thought to be the DNA modifications, which can be come permanent via the formation of mutations and other types of genomic in stability. Many different DNA base changes have been seen following some fo rm of oxidative stress, and these lesions are widely considered as instigat ors for the development of cancer and are also implicated in the process of aging. Several studies have documented that oxidative DNA lesions accumula te with aging, and it appears that the major site of this accumulation is m itochondrial DNA rather than nuclear DNA. The DNA repair mechanisms involve d in the removal of oxidative DNA lesions are much more complex than previo usly considered. They involve base excision repair (BER) pathways and nucle otide excision repair (NER) pathways, and there is currently a great deal o f interest in clarification of the pathways and their interactions. We have used a number of different approaches to explore the mechanism of the repa ir processes, and we are able to examine the repair of different types of l esions and to measure different steps of the repair processes. Furthermore, we can measure the DNA damage processing in the nuclear DNA and separately , in the mitochondrial DNA. Contrary to widely held notions, mitochondria h ave efficient DNA repair of oxidative DNA damage and we are exploring the m echanisms. In a human disorder, Cockayne syndrome (CS), characterized by pr emature aging, there appear to be deficiencies in the repair of oxidative D NA damage in the nuclear DNA, and this may be the major underlying cause of the disease. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.