Non-transcriptional control of DNA replication by c-Myc.
Dominguez-Sola, David 1*; Ying, Carol Y. 1*; Grandori, Carla 2+; Ruggiero, Luca 1; Chen, Brenden 1; Li, Muyang 1; Galloway, Denise A. 2; Gu, Wei 1; Gautier, Jean 1*; Dalla-Favera, Riccardo 1*
[Article] Nature. 448(7152):445-451, July 26, 2007.

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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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