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The centromere is a region involved in cell division and control of gene expression.Centromeres of higher eukaryotes are defined by typical tandem repetitive sequences of hundreds to thousands of kilobases, often called "satellite DNA".The alpha satellite arrays in human centromeres extend over millions of base pairs and are composed of highly homogeneous repeats of the 170 bp monomer.Such DNA poses two problems: the repeats can spontaneously multiply or shrink in the cell, and it is almost impossible to accurately sequence them.Extrachromosomal circular DNA (eccDNA) is a heterogeneous population of circular double stranded DNA molecules found at high levels in tumors and in aging cells.Studying eccDNA in mouse tumor cells we have recently shown that most eccDNA molecules are composed of major satellite DNA (MSD) derived from the pericentromeric region.Our recent in-vitro studies suggest that eccDNA molecules are excised from the genome.A predicted outcome of such process is the loss of genetic material from the centromeric and pericentromeric regions and shortening of the chromosome from within.We propose that eccDNA appearance reflects a profound mechanism, "chromosome shriveling".The loss of genetic material from the centromere leads to its shrinkage.Some or all of the excised centromeric repeats might form the eccDNA To examine this hypothesis we established an in vivo system in the yeast Saccharomyces cerevisiae.A yeast artificial chromosome (YAC) carrying a cluster of 70 MSD repeats was established in the yeast cells.Biochemical analysis revealed that the MSD region was extremely unstable and deletions occurred at very high frequency (1/5).These deletions were associated with the formation ofeccDNA consisting of the MSD repeats.