A nontranscriptional role for HIF-1α as a direct inhibitor of DNA replication

Maimon E. Hubbi, Kshitiz, Daniele M. Gilkes, Sergio Rey, Carmen C. Wong, Weibo Luo, Deok Ho Kim, Chi V. Dang, Andre Levchenko, Gregg L. Semenza

Research output: Contribution to journalArticle

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-1b 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.

Original languageEnglish (US)
Article numberra10
JournalScience signaling
Volume6
Issue number262
DOIs
StatePublished - Feb 12 2013

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Hubbi, M. E., Kshitiz, Gilkes, D. M., Rey, S., Wong, C. C., Luo, W., Kim, D. H., Dang, C. V., Levchenko, A., & Semenza, G. L. (2013). A nontranscriptional role for HIF-1α as a direct inhibitor of DNA replication. Science signaling, 6(262), [ra10]. https://doi.org/10.1126/scisignal.2003417