EXPRESSION OF FRAGILE SITES TRIGGERS INTRACHROMOSOMAL MAMMALIAN GENE AMPLIFICATION AND SETS BOUNDARIES TO EARLY AMPLICONS

Drug-selected intrachromosomal gene amplification by breakage-fusion-b ridge (BFB) cycles is well documented in mammalian cells, but factors governing this mechanism are not clear. Here, we show that only some c lastogenic drugs induce drug resistance through intrachromosomal ampli fication. We strictly correlate triggering of BFB cycles to induction of fragile site expression. We demonstrate a dual role for fragile sit es 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 fragi le sites relative to boundaries of amplicons found in human cancers su pport the hypothesis that fragile sites play a key role in the amplifi cation of at least some oncogenes during tumor progression.