Re-replication generates whole-chromosomal instability and anueploidy

Aneuploidy, a hallmark of cancer, often arises from whole-chromosomal instability (W-CIN). Many cancers exhibiting W-CIN, however, show no direct insult to the mitotic proteins that ensure proper segregation of chromosomes. This has stimulated interest in identifying defects in non-mitotic processes that might disrupt chromosome behavior in mitosis. Here we show in Saccharomyces cerevisiae that transient re-replication of centromeric DNA, due to deregulation of replication initiation proteins, greatly induces aneuploidy of the rereplicated chromosome. Some of this aneuploidy appears to arise from simple missegregation of both sister chromatids to one daughter cell, indicating that centromeric re-replication can disrupt proper centromere function during mitosis. Another source of aneuploidy appears to be the generation of an extra sister chromatid via homologous recombination, suggesting that centromeric rereplication can trigger breakage and repair events that expand chromosome numbers while preserving chromosome structure. Given the emerging connections between the deregulation of replication initiation proteins and oncogenesis, our findings offer the possibility of a new non-mitotic source of aneuploidy that may be relevant to cancer. Diploid strains containing a re-replicating locus were induced to re-replicate through a centromere. This compilation includes the analysis of the re-replication, as well as the copy-number determination of alleged aneuploid colonies from various backgrounds. Series contains a total of 194 copy number hybridizations and 8 re-replication profile hybridizations. Note that the VALUE field reported for all of the sample tables in this series are the log2 of the normalized Cy3/Cy5 ratio. To convert these into usable copy number profiles raise 2 to the indicated VALUE.