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Micronuclei Formation with Chromosome Breaks and Gene Amplification Caused by Vpr, an Accessory Gene of Human Immunodeficiency Virus¹

Department of Intractable Diseases, International Medical Center of Japan, Tokyo 162-8655 [M. S., Y. I.]; Biomedical Laboratories, Inc., Saitama 350-1101, [Y. O., T. Y.]; and Jichi Medical School, Tochigi 329-0498 [K. H., F. T.], Japan

Vpr, an accessory gene of human immunodeficiency virus, induces cell cycle abnormality by accumulating cells at the G₂-M phase. We reported recently that Vpr caused both micronuclei formation and aneuploidy. Here, we show that Vpr also induced chromosome breaks and gene amplification. Expression of Vpr induced more than 10-fold increase of colonies resistant to N-(phosphonacetyl)-L-aspartate, an inhibitor of pyrimidine de novo synthesis. Fluorescence in situ hybridization analysis detected that 4 of 10 N-(phosphonacetyl)-L-aspartate resistant clones studied had intrachromosomal amplification of carbamyl-phosphate synthetase/aspartate transcarbamoylase/dihydroorotase gene. Another single clone had dicentrics. Data suggested that the Vpr-induced chromosome breaks leading to gene amplification, followed by bridge-breakage-fusion cycle, were one of the possible mechanisms of Vpr-induced genomic instability.

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