The role of nucleotides in human fragile site expression

Fragile sites are points on chromosomes which tend to break non-randomly when exposed to specific chemical agents or conditions of tissue culture. There are 3 groups of rare fragile sites, and carriers of these range in incidence from about 1 in 20 to 1 in several thousand individuals. Rare fragile sites are essentially chromosome variants with no known phenotypic consequence, except for the fragile X which is associated with the commonest inherited form of mental retardation in man. There are also 3 groups of common fragile sites, carried by all or most individuals. These are part of normal chromosomal architecture. Expression of most of the groups of fragile sites is mediated by perturbations of the nucleotide pool and these, as they relate to each group of fragile sites, are discussed. The rare folate-sensitive fragile sites are expressed when thymidylate or deoxycytidine are in limited supply during DNA synthesis. Other rare fragile sites are induced by bromodeoxyuridine (BrdU). Sets of common fragile sites are induced by BrdU, 5-azacytidine and aphidicolin. Various hypotheses on the molecular nature of fragile sites are considered.