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.
Yunis
J J
JJ
Department of Neoplastic Diseases, Hahnemann University School of Medicine, Philadelphia.
Hoffman
W R
WR
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D004262:DNA Restriction Enzymes / Q000494:pharmacology*; D003850:Deoxyribonuclease I / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D009153:Mutagens / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics*
D002273:Carcinogens; D009153:Mutagens; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D004262:DNA Restriction Enzymes; D003850:Deoxyribonuclease I