Double minute chromosomes can be produced from precursors derived from a chromosomal deletion.

Abstract

Recent experiments have shown that gene amplification can be mediated by submicroscopic, autonomously replicating, circular extrachromosomal molecules. We refer to those molecules as episomes (S. Carroll, P. Gaudray, M. L. DeRose, J. F. Emery, J. L. Meinkoth, E. Nakkim, M. Subler, D. D. Von Hoff, and G. M. Wahl, Mol. Cell. Biol. 7:1740-1750. The experiments reported in this paper explore the way episomes are formed and their fate in the cell over time. The data reveal that in our system the episomes are initially 250 kilobases, but gradually enlarge until they become double minute chromosomes. In addition, we show that episomes or double minute chromosomes can integrate into chromosomes. Our results also suggest that episomes can be produced by deletion of the corresponding sequences from the chromosome.

Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia

“…1a,b and Table 1). Similar deletions associated with amplification of MYC on dmin chromosomes or episomes have been reported 12 .…”

Double minute chromosomes carrying the human multidrug resistance 1 and 2 genes are generated from the dimerization of submicroscopic circular DNAs in colchicine-selected KB carcinoma cells.

“…In addition, in vitro studies imply that many of the structural chromosomal abnormalities occurring in tumors and tumorigenic cell lines (Bishop, 1987;Tlsty et al, 1989) may result from molecular mechanisms common to those mediating extrachromosomal gene amplification. For example, recent studies have provided firm evidence that some extrachromosomal elements have the potential to integrate into chromosomes, resulting in either HSRs, ECRs (Carroll et al, 1988;Ruiz and Wahl, 1990;Von Hoff et al, 1990;Windle et al, 1991), or other chromosome abnormalities such as ring chromosomes (Windle et al, 1991). These studies support earlier observations of gene amplification in hamster cell lines in which Biedler (1982) observed that the extrachromosomal circular DMs rapidly integrated into chromosomes, resulting in HSR structures (Biedler, 1982).…”

“…Amplification of a region of DNA via an extrachromosomal element often results in a deletion at the corresponding chromosomal locus (Carroll et al, 1988;Hunt et al, 1990;Heard et al, 1991). If a deletion is present, its respective size could provide information as to the size of the initial amplicon.…”

“…Several studies of cultured cell lines have provided a molecular chronology of events in which submicroscopic circular DNAs precede the appearance of cytogenetically detectable DM structures (Carroll et al, 1987(Carroll et al, , 1988. In addition, pulsed-field gel electrophoresis (PFGE) data from neuroblastoma biopsies imply that the multimerization of MYCN circles in vivo can generate DM structures .…”

Induction of multiple double-strand breaks within an hsr by meganucleaseI-SceI expression or fragile site activation leads to formation of double minutes and other chromosomal rearrangements

“…These studies led to the identification of at least two different initial gene amplification mechanisms (Coquelle et al, 1997;Carroll et al, 1988;Ma et al, 1993;Ruiz and Wahl, 1988;Smith et al, 1992;Toledo et al, 1992Toledo et al, , 1993Trask and Hamlin, 1989;Windle et al, 1991). The breakage-fusion-bridge (BFB) cycle mechanism, first described by McClintock (1942), accumulates copies organized as large inverted repeats on a chromosome arm where one normal gene copy maps in non-amplified cells (Coquelle et al, 1997;Ma et al, 1993;Toledo et al, 1992Toledo et al, , 1993.…”