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  • Original Paper
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c-Myc initiates illegitimate replication of the ribonucleotide reductase R2 gene

Oncogene volume 21, pages 909–920 (2002)Cite this article

Abstract

The mechanisms through which the oncoprotein c-Myc initiates locus-specific gene amplification are not understood. When analysing the initiation mechanism of c-Myc-dependent amplification of the mouse ribonucleotide reductase R2 (R2) gene, we observe c-Myc-dependent initiation of illegitimate DNA replication of the R2 gene. We demonstrate multiple simultaneous c-Myc-induced R2 replication forks, whereas R2 normally replicates with a single fork. In contrast, cyclin C replicates with only a single replication fork irrespective of c-Myc deregulation. In addition to de novo replication forks, c-Myc also initiates bi-allelic replication of R2, abrogating its normal mono-allelic replication pattern. Moreover, several chromosomal regions also display c-Myc-induced illegitimate replication profiles. Thus, c-Myc can act as an illegitimate replication-licensing factor that promotes de novo replication initiation and illegitimate replication timing that adversely impacts upon genomic stability.

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Acknowledgements

The authors thank Mrs Mary Cheang (Biostatistical Consulting Unit, Department of Community Health Services, Faculty of Medicine, University of Manitoba) for statistical analysis. We thank our colleagues, Drs A Begleiter, GG Hicks, T Fest and JF Mushinski, for critical reading of this manuscript. TI Kuschak was supported by a GH Sellers Graduate studentship awarded through CancerCare Manitoba. S Mai and JA Wright were funded through the National Science and Engineering Research Council of Canada (S Mai NSERC grant # 311-3135-03; JA Wright NSERC grant # 311-1735-05), and the Medical Research Council (JA Wright MRC grant # 321-3119-70, S Mai CIHR grant # 321-3135-19).

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Authors and Affiliations

  1. Department of Microbiology, The University of Manitoba, The Manitoba Institute of Cell Biology, The Genomic Centre for Cancer Research and Diagnosis and CancerCare Manitoba, 675 McDermot Ave., Winnipeg, R3E 0V9, MB, Canada

    T I Kuschak

  2. Manitoba Institute of Cell Biology, The University of Manitoba, The Genomic Centre for Cancer Research and Diagnosis, and CancerCare Manitoba, 675 McDermot Ave., Winnipeg, R3E 0V9, MB, Canada

    B C Kuschak, C L Taylor, J A Wright & S Mai

  3. Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm, P.O. Box 280, S17177, Sweden

    F Wiener

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  1. T I Kuschak
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Correspondence to S Mai.

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Kuschak, T., Kuschak, B., Taylor, C. et al. c-Myc initiates illegitimate replication of the ribonucleotide reductase R2 gene. Oncogene 21, 909–920 (2002). https://doi.org/10.1038/sj.onc.1205145

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