Nuclear enzymes, fragile sites, and cancer

The finding of a large number of recurrent fragile sites on human chromosomes provides suggestive evidence for the origin of recurrent chromosomal rearrangements that are a common feature in most neoplasias. These fragile sites can be induced by a wide variety of mutagens and carcinogens that are known to act through different molecular mechanisms. They correlate with two-thirds of the recurrent cancer chromosomal breakpoints known thus far and with the location of most mapped oncogenes and growth factors. Because we have now found that a large number of fragile sites can also be induced by agents such as DNase I and benzo[a]pyrene diol-epoxide (BPDE), which are known to induce hypersensitive chromatin sites, it is possible that a class of fragile sites represents regulatory regions of active genes. We have also introduced restriction enzymes into cultured lymphocytes and found that fragile sites are expressed in a pattern similar to that produced by DNase I and BPDE. Because fragile sites have a higher expression with advancing age, cigarette smoking, and deficiency of folic acid and B12 vitamins, they may represent active genomic sites that are vulnerable to physiological and environmental disturbance.