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A single acute exposure to a chemotherapeutic agent induces hyper-recombination in distantly descendant cells and in their neighbors

Oncogene volume 24, pages 5016–5025 (2005)Cite this article

Abstract

Homologous recombination can induce tumorigenic sequence rearrangements. Here, we show that persistent hyper-recombination can be induced following exposure to a bifunctional alkylating agent, mitomycin C (MMC), and that the progeny of exposed cells induce a hyper-recombination phenotype in unexposed neighboring cells. Residual damage cannot be the cause of delayed recombination events, since recombination is observed after drug and template damage are diluted over a million-fold. Furthermore, not only do progeny of MMC-exposed cells induce recombination in unexposed cells (bystanders), but these bystanders can in turn induce recombination in their unexposed neighbors. Thus, a signal to induce homologous recombination can be passed from cell to cell. Although the underlying molecular mechanism is not yet known, these studies reveal that cells suffer consequences of damage long after exposure, and that can signal unexposed neighboring cells to respond similarly. Thus, a single acute exposure to a chemotherapeutic agent can cause long-term changes in genomic stability. If the results of these studies of mouse embryonic stem (ES) cells are generally applicable to many cell types, these results suggest that a relatively small number of cells could potentially induce a tissue-wide increase in the risk of de novo homologous recombination events.

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Acknowledgements

For assistance in statistics, we thank Dr AJ Engelward of the Department of Mathematics, Harvard University. We thank Laura Trudel for technical help in the preparation of this manuscript and Dr E Spek for assistance in creating the HPRT targeting construct and for helpful comments on the manuscript. We thank Laurel Vuong and Jeff Loh for technical support in developing the fluorescence based recombination assay. The Engelward lab is supported by CA84740 and the Burroughs Wellcome Fund. We thank L Samson and the MIT Center for Environmental Health Sciences for supporting this work (P30-ES02109).

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  1. Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA

    Rebecca E Rugo, Karen H Almeida, Carrie A Hendricks, Vidya S Jonnalagadda & Bevin P Engelward

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  1. Rebecca E Rugo
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  2. Karen H Almeida
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Correspondence to Bevin P Engelward.

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Rugo, R., Almeida, K., Hendricks, C. et al. A single acute exposure to a chemotherapeutic agent induces hyper-recombination in distantly descendant cells and in their neighbors. Oncogene 24, 5016–5025 (2005). https://doi.org/10.1038/sj.onc.1208690

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