GENE AMPLIFICATION AND CHROMOSOMAL REARRA NGEMENTS DURING ACQUISITIONOF RESISTANCE TO AN ANTIMETABOLITE, COFORMYCIN

We studied the early stages of gene amplification in a Chinese hamster cell line and we show that two distinct mechanisms can operate at a s ingle locus. Both of them rely on an unequal segregation of gene copie s at mitosis. We conclude that cycles of chromatid breakage, followed by fusion of sister chromatids devoided of a telomere that lead to fur ther breaks in mitosis, have a key role in the coupling of gene amplif ication and genome remodeling. Rearrangements are first limited to a s ingle chromosome but can then potentially spread to any additional chr omosome. Occasionally, a sequence containing the selected gene can be looped out, generating a ''double minute'' and thus initiating an inde pendent process of extrachromosomal amplification.