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Loss Of DNA Replication Control Is A Potent Inducer Of Gene Amplification

B. Green, Kenneth J. Finn, J. Li
Published 2010 · Biology, Medicine

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The Pitfalls of Re-Replication The cell has several layers of regulation to ensure that the genome is replicated once and only once during cell division, presumably to avoid the formation of duplicated sequences, which have the potential to recombine and compromise genome stability. In agreement with this idea, Green et al. (p. 943; see the Perspective by Kaochar et al.) now show that re-replication of a marked yeast replication origin causes a significant increase in copy number variation in the region encompassing the origin. The observed duplications range in size from 135 to 470 kilobases and are almost all tandemly arrayed in a head-to-tail orientation. The duplicated regions are bounded by Ty repetitive elements and arise from nonallelic homologous recombination between the re-replicated repetitive elements. Re-replication of DNA and homologous recombination between repetitive elements can cause genome instability. Eukaryotic cells use numerous mechanisms to ensure that no segment of their DNA is inappropriately re-replicated, but the importance of this stringent control on genome stability has not been tested. Here we show that re-replication in Saccharomyces cerevisiae can strongly induce the initial step of gene amplification, increasing gene copy number from one to two or more. The resulting amplicons consist of large internal chromosomal segments that are bounded by Ty repetitive elements and are intrachromosomally arrayed at their endogenous locus in direct head-to-tail orientation. These re-replication–induced gene amplifications are mediated by nonallelic homologous recombination between the repetitive elements. We suggest that re-replication may be a contributor to gene copy number changes, which are important in fields such as cancer biology, evolution, and human genetics.
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