Inherited defects in DNA repair and susceptibility to DNA-damaging agents.

Since all organisms are continuously exposed to exogenous and endogenous DNA damaging agents, mechanisms of repair of DNA lesions are necessary to maintain the integrity of the genome. Studies of the cellular defects in human inherited diseases with deficiencies in DNA repair have given new insights into these processes. Nucleotide excision repair is an important DNA repair pathway in which several types of DNA lesions are removed by a multi-step enzymatic process. This repair mechanism is deficient in the rare disease xeroderma pigmentosum (XP), which results in extreme sensitivity to ultraviolet light (UV) and development of UV-induced skin tumors at an early age. There are several genetic complementation groups of XP. The genes that are mutated in some of the XP complementation groups have been cloned and the functions of the encoded proteins are being characterised. Several types of DNA lesions are removed more rapidly from active genes than from other regions of DNA. This preferential repair of active genes is deficient in Cockayne's syndrome, which is characterised by developmental abnormalities and UV-sensitivity but no marked increase in cancer incidence. Other syndromes associated with increased sensitivity to certain DNA damaging agents where no defect in DNA repair has been defined include Fanconi's anemia (sensitivity to DNA cross-linking agents), hereditary dysplastic nevus syndrome (sensitivity to UV) and ataxia-telangiectasia (sensitivity to ionizing radiation).