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J. Cell Biol.,
Volume 140, Number 6, March 23, 1998 1307-1320
* Faculty of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima, 724, Japan; and Acentric, autonomously replicating extrachromosomal structures called double-minute chromosomes (DMs) frequently mediate oncogene amplification in human tumors. We show that DMs can be
removed from the nucleus by a novel micronucleation
mechanism that is initiated by budding of the nuclear
membrane during S phase. DMs containing c-myc oncogenes in a colon cancer cell line localized to and replicated at the nuclear periphery. Replication inhibitors increased micronucleation; cell synchronization and
bromodeoxyuridine-pulse labeling demonstrated de
novo formation of buds and micronuclei during S
phase. The frequencies of S-phase nuclear budding and micronucleation were increased dramatically in normal
human cells by inactivating p53, suggesting that an
S-phase function of p53 minimizes the probability of
producing the broken chromosome fragments that induce budding and micronucleation. These data have
implications for understanding the behavior of acentric
DNA in interphase nuclei and for developing chemotherapeutic strategies based on this new mechanism for
DM elimination.
Gene Expression
Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037
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