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Inactivation of the RRB1-Pescadillo pathway involved in ribosome biogenesis induces chromosomal instability

Oncogene volume 23, pages 8597–8602 (2004)Cite this article

Abstract

Since chromosomal instability (CIN) is a hallmark of most cancer cells, it is essential to identify genes whose alteration results into this genetic instability. Using a yeast CIN indicator strain, we show that inactivation of the YMR131c/RRB1 gene, which is involved in early ribosome assembly and whose expression is induced when the spindle checkpoint is activated, alters chromosome segregation and blocks mitosis at the metaphase/anaphase transition. We demonstrate that RRB1 interacts with YPH1 (yeast pescadillo homologue 1) and other members of the Yph1 complex, RPL3, ERB1 and ORC6, involved in ribosome biogenesis and DNA replication. Transient depletion of the human homologues GRWD, Pescadillo, Rpl3, Bop1 and Orc6L resulted in an increase of abnormal mitoses with appearance of binucleate or hyperploid cells, of cells with multipolar spindles and of aberrant metaphase plates. If deregulation of proteins involved in ribosome biogenesis, commonly observed in malignant tumors, could contribute to cancer through an aberrant protein synthesis, our study demonstrates that alteration of proteins linking ribosome biogenesis and DNA replication may directly cause CIN.

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Acknowledgements

We are indebted to René Gantier for his assistance in protein structure analysis, to Pascal Roussel for fruitful discussions, to Mario Tosi for critical review of the manuscript and to Richard Morrison for the gift of the Pescadillo antibody. This work was supported by l’Association pour la Recherche sur le Cancer, la Fondation pour la Recherche Médicale and la Ligue Nationale contre le Cancer. AK was supported by a grant from le Ministère de la Recherche.

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  1. Audrey Killian and Nathalie Le Meur: These authors contributed equally to this work

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM) U 614 – IFRMP, Faculty of Medicine, 22 Boulevard Gambetta, Rouen Cedex, 76183, France

    Audrey Killian, Nathalie Le Meur, Richard Sesboüé, Jeannette Bourguignon, Gaëlle Bougeard, Julien Gautherot, Christian Bastard, Thierry Frébourg & Jean-Michel Flaman

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  1. Audrey Killian
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Correspondence to Thierry Frébourg.

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Killian, A., Meur, N., Sesboüé, R. et al. Inactivation of the RRB1-Pescadillo pathway involved in ribosome biogenesis induces chromosomal instability. Oncogene 23, 8597–8602 (2004). https://doi.org/10.1038/sj.onc.1207845

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