title: A nontranscriptional role for HIF-1α as a direct inhibitor of DNA replication.
abstract: Cell cycle arrest in response to hypoxia is a fundamental physiological mechanism to maintain a balance between O(2) supply and demand. Many of the cellular responses to reduced O(2) 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.
authors: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Maimon E
authors: ME
authors: Hubbi
authors: Kshitiz
authors: Daniele M
authors: DM
authors: Gilkes
authors: Sergio
authors: S
authors: Rey
authors: Carmen C
authors: CC
authors: Wong
authors: Weibo
authors: W
authors: Luo
authors: Deok-Ho
authors: DH
authors: Kim
authors: Chi V
authors: CV
authors: Dang
authors: Andre
authors: A
authors: Levchenko
authors: Gregg L
authors: GL
authors: Semenza
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D004261:DNA Replication; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D014158:Transcription, Genetic
chemical_list: C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins
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