Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons.
Drug-selected intrachromosomal gene amplification by breakage-fusion-bridge (BFB) cycles is well documented in mammalian cells, but factors governing this mechanism are not clear. Here, we show that only some clastogenic drugs induce drug resistance through intrachromosomal amplification. We strictly correlate triggering of BFB cycles to induction of fragile site expression. We demonstrate a dual role for fragile sites in intrachromosomal amplification: a site telomeric to the selected gene is involved in initiation, while a centromeric site defines the size and organization of early amplified units. The positions of fragile sites relative to boundaries of amplicons found in human cancers support the hypothesis that fragile sites play a key role in the amplification of at least some oncogenes during tumor progression.
Coquelle
A
A
Centre National de la Recherche Scientifique, Institut Pasteur, Paris, France.
Pipiras
E
E
Toledo
F
F
Buttin
G
G
Debatisse
M
M
D000659:AMP Deaminase / Q000235:genetics; D000243:Adenosine Deaminase / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D003070:Coformycin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage; D003609:Dactinomycin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005784:Gene Amplification / Q000187:drug effects / Q000235:genetics*; D019450:Genes, MDR / Q000235:genetics; D008727:Methotrexate / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014747:Vinblastine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D009153:Mutagens; D003070:Coformycin; D003609:Dactinomycin; D014747:Vinblastine; D004317:Doxorubicin; D013762:Tetrahydrofolate Dehydrogenase; D000243:Adenosine Deaminase; D000659:AMP Deaminase; D008727:Methotrexate