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Sci. Signal., 12 February 2013
Vol. 6, Issue 262, p. ra10
[DOI: 10.1126/scisignal.2003417]

RESEARCH ARTICLES

A Nontranscriptional Role for HIF-1α as a Direct Inhibitor of DNA Replication

Maimon E. Hubbi1,2*, Kshitiz1,3,4*, Daniele M. Gilkes1,2, Sergio Rey1,2, Carmen C. Wong1,2, Weibo Luo1,5, Deok-Ho Kim4, Chi V. Dang6, Andre Levchenko1,3, and Gregg L. Semenza1,2,5,6,7{dagger}

1 Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3 Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
4 Department of Bioengineering, School of Medicine, University of Washington, Seattle, WA 98195, USA.
5 Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6 Departments of Medicine and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
7 Departments of Pediatrics and Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

* These authors contributed equally to this work.

Abstract: Cell cycle arrest in response to hypoxia is a fundamental physiological mechanism to maintain a balance between O2 supply and demand. Many of the cellular responses to reduced O2 availability are mediated through the transcriptional activity of hypoxia-inducible factor 1 (HIF-1). We report a role for the isolated HIF-1α subunit as an inhibitor of DNA replication, and this role was independent of HIF-1β and transcriptional regulation. In response to hypoxia, HIF-1α bound to Cdc6, a protein that is essential for loading of the minichromosome maintenance (MCM) complex (which has DNA helicase activity) onto DNA, and promoted the interaction between Cdc6 and the MCM complex. Although the interaction between Cdc6 and the MCM complex increased the association of the MCM proteins with chromatin, the binding of HIF-1α to the complex decreased phosphorylation and activation of the MCM complex by the kinase Cdc7. As a result, HIF-1α inhibited firing of replication origins, decreased DNA replication, and induced cell cycle arrest in various cell types. These findings establish a transcription-independent mechanism by which the stabilization of HIF-1α leads to cell cycle arrest in response to hypoxia.

{dagger} To whom correspondence should be addressed. E-mail: gsemenza{at}jhmi.edu

Citation: M. E. Hubbi, Kshitiz, D. M. Gilkes, S. Rey, C. C. Wong, W. Luo, D.-H. Kim, C. V. Dang, A. Levchenko, G. L. Semenza, A Nontranscriptional Role for HIF-1α as a Direct Inhibitor of DNA Replication. Sci. Signal. 6, ra10 (2013).

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