DNA repair fine structure and its relations to genomic instability.

It is timely to review aspects of DNA repair as there have recently been major advances in this field. These insights have provided information regarding new linkages between DNA repair defects and cancer. Several human repair genes have been identified and cloned, and a direct molecular connection has been established between DNA repair and transcription. The main focus of this review is to examine some new molecular relationships that have emerged pursuant to recent advances in the understanding of the fine structure of DNA repair processes. In particular, relations to genomic instability will be emphasized. Genomic instability is an important hallmark of both cancer and the ageing process, and is a broad term that includes a number of more or less specific changes in DNA. They can be point mutations, deletions, hypermutability, hypermethylation (epimutations), chromosomal rearrangements and/or abnormalities, or degradation of DNA. One form of genomic instability, the dysregulation of the cell cycle progression, affects mutational rates. Forms of DNA damage The classic DNA-damaging agent of interest has been UV light which introduces two major photolesions in DNA: the cyclobutane dimer and the 6-4 photoproduct. These lesions are directly linked to skin cancer, because patients with deficiencies in the repair of photolesions develop carcinoma in skin exposed to UV (1). Other bulky lesions in DNA that have been widely studied include those made by carcinogens such as 4-nitroquinol ine-A/-oxide (4NQO*), A'-acetoxyacetylaminofluorene (NAAF), and alkylating agents such as nitrogen mustard (HN2). Several chemotherapeutic agents used to treat tumors directly damage the DNA. Such agents include alkylating agents and cisplatin. These compounds form intrastrand adducts (IA) in DNA and less frequently, interstrand crosslinks (ICL). Recently, there has been an increasing interest in oxidative DNA damage and its consequences. Reactive oxygen species are constantly generated by cellular metabolism, radiation, drugs, mitochondria and chemicals. The oxidative DNA lesions that are formed probably constitute the most common forms of DNA damage and are likely to be important in tumor initiation and/or promotion. Studies show that > 100 different lesions are formed in DNA after oxidative stress (2).