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Non-transcriptional control of DNA replication by c-Myc

Nature volume 448, pages 445–451 (2007)Cite this article

An Author Correction to this article was published on 29 June 2023

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Abstract

The c-Myc proto-oncogene encodes a transcription factor that is essential for cell growth and proliferation and is broadly implicated in tumorigenesis. However, the biological functions required by c-Myc to induce oncogenesis remain elusive. Here we show that c-Myc has a direct role in the control of DNA replication. c-Myc interacts with the pre-replicative complex and localizes to early sites of DNA synthesis. Depletion of c-Myc from mammalian (human and mouse) cells as well as from Xenopus cell-free extracts, which are devoid of RNA transcription, demonstrates a non-transcriptional role for c-Myc in the initiation of DNA replication. Overexpression of c-Myc causes increased replication origin activity with subsequent DNA damage and checkpoint activation. These findings identify a critical function of c-Myc in DNA replication and suggest a novel mechanism for its normal and oncogenic functions.

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Figure 1: Myc interacts with the pre-replicative complex in mammalian cells.
Figure 2: Myc co-localizes with early DNA synthesis foci and binds the Myc gene replication origin.
Figure 3: Myc is required for efficient DNA replication and proper origin specification in the absence of transcription.
Figure 4: Relationship between Myc protein levels and the number of active DNA replication origins.
Figure 5: Myc deregulation induces replication-dependent DNA damage.

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Acknowledgements

We thank R. Baer for critical reading of the manuscript; J. Walter and H. Nishitani for Xenopus Cdc45 and human Cdt1 antibodies; W. M. Michael for DNA polymerase α antibodies; D. Shechter for NPE and technical suggestions; A. Lasorella and A. Iavarone for N-Myc plasmids; G. S. Martin and T. Prathapam for 3T9 c-myc+/- cells; W. Zhang for mass spectrometry analysis; P. Liccardo for generating the Myc H1299 cell line; G. Cattoreti, P. Smith and J. Kosek for technical advice with the immunofluorescence; H. Morse for providing the λ-Myc mouse strain; U. Klein and L. Pasqualucci for advice on mouse B-cell isolation; C. Li for Myc siRNA sequences; M. Lia for GAPDH primers; C. Franci for advice on peptide selection for XMyc antibody; and K. Robinson for technical help with ChIP, quantitative PCR and deconvolution microscopy analysis. This work was supported by grants from the National Institutes of Health (to R.D.-F. and J.G.) and the American Cancer Society (to J.G.). D.D.-S. was a recipient of a postdoctoral grant from Fundacio “la Caixa” (Spain).

Author Contributions R.D.-F. and J.G. supervised the entire project and contributed equally as co-senior authors; D.D.-S. designed and conducted the experiments in mammalian cells; D.D.-S. and C.Y.Y. designed the experiments in Xenopus, which were conducted by C.Y.Y.; D.D.-S. and C.Y.Y. wrote the manuscript under the supervision of R.D.-F. and J.G. and comments from all co-authors; C.G. designed and conducted immunofluorescence and ChIP experiments in human primary cells; B.C. and M.L. conducted the initial purification and chromatography of the Myc complex, designed and supervised by W.G.; and L.R. contributed to the biochemical characterization of the complex.

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Author notes

  1. Carla Grandori

    Present address: Present address: Rosetta Inpharmatics, Merck, Seattle, Washington 98109, USA.,

  2. David Dominguez-Sola, Carol Y. Ying, Jean Gautier and Riccardo Dalla-Favera: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics and Development and Herbert Irving Comprehensive Cancer Center, Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA,

    David Dominguez-Sola, Carol Y. Ying, Luca Ruggiero, Brenden Chen, Muyang Li, Wei Gu, Jean Gautier & Riccardo Dalla-Favera

  2. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA,

    Carla Grandori & Denise A. Galloway

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Dominguez-Sola, D., Ying, C., Grandori, C. et al. Non-transcriptional control of DNA replication by c-Myc. Nature 448, 445–451 (2007). https://doi.org/10.1038/nature05953

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