Mammalian nucleotide excision repair and syndromes

A variety of endogenous and environmental events threaten the integrity of genetic material. The intrinsic instability of DNA, along with metabolites, natural and man-made chemicals, X-rays and UV light may all alter the structure of the DNA molecule. Persistent DNA damage can disrupt vital cellular processes, such as DNA replication and transcription. To counteract the deleterious effects of DNA damage, several DNA-repair mechanisms have evolved [1]. One of the most versatile DNA-repair mechanisms is nucleotide excision repair (NER) [2]. This repair pathway is able to remove a broad spectrum of structurally unrelated DNA lesions in a multi-step fashion requiring the action of a large number of nuclear activities. The overall mechanism of NER has been conserved during evolution, with structural and functional conservation being observed even between yeast and man. The process can be divided into roughly three distinct steps: (1) damage recognition and demarcation; (2) removal of the damage by a dual incision (exci-sion) in the damaged strand on either side of the lesion; (3) gap filling, using the opposite undam-aged strand as a template, and turnover of the excision complex. Cloning of the mammalian NER genes and biochemical characterization of the gene products using in vitro [3] and in vivo (4] DNA-repair assays has resulted in the development of a detailed model of the reaction mechanism.