Phenotypic and Genetic Heterogeneity in Fanconi Anemia, Fate of Cross-Links, and Correction of the Defect by DNA Transfection

The isolation and characterization of mutants unusually susceptible to DNA- damaging agents in prokaryotes and in lower eukaryotes helped considerably in the unraveling of the mystery of the genetic control mechanism and metabolic steps of DNA repair functions (for review see Friedberg 1985). The lack of available mutant cells defective in their response to DNA damage hampered for similar studies in human cells many years. The first indication of a DNA repair defect associated with an inherited human disease was found by Cleaver in 1968. The unusual sensitivity to sun of fibroblasts from a patient with the disease xeroderma pigmentosum (XP) was found to be associated with an excision defect of DNA lesions. This observation stimulated great interest in examination of the response to DNA-damaging agents in the cells from patients with a number of other hereditary diseases, particularly those associated with chromosomal abnormalities and with a high incidence of neoplasia (for reviews see Friedberg et al. 1979; Hanawalt and Sarasin 1986). Since then, a number of diseases other than XP have been shown to be abnormal in their response to DNA-damaging agents. It should be kept in mind, however, that an abnormal sensitivity of cells to killing by physical and/or chemical agents interacting with DNA does not necessarily imply a specific defect in DNA repair. An imbalance in DNA biosynthesis and replication, membrane defect(s) interfering with nuclear function(s), the abnormal production of endogenous metabolic products that damage DNA, or mitochondrial susceptibility to agents may create increased cellular sensitivity.