Coquelle A, Pipiras E, Toledo F, Buttin G, Debatisse M
Centre National de la Recherche Scientifique, Institut Pasteur, Paris, France.
Cell. 1997 Apr 18;89(2):215-25. doi: 10.1016/s0092-8674(00)80201-9.
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.
通过断裂-融合-桥接（BFB）循环进行的药物选择的染色体内基因扩增在哺乳动物细胞中已有充分记录，但控制这一机制的因素尚不清楚。在这里，我们表明只有一些致断裂药物通过染色体内扩增诱导耐药性。我们将BFB循环的触发与脆性位点表达的诱导严格关联起来。我们证明了脆性位点在染色体内扩增中的双重作用：所选基因端粒处的位点参与起始，而着丝粒位点则决定早期扩增单元的大小和组织。脆性位点相对于人类癌症中发现的扩增子边界的位置支持了这样一种假说，即脆性位点在肿瘤进展过程中至少对某些癌基因的扩增起关键作用。
