A nontranscriptional role for HIF-1α as a direct inhibitor of DNA replication.
A nontranscriptional role for HIF-1α as a direct inhibitor of DNA replication.
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DOI：
10.1126/scisignal.2003417
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发表时间：
2013-02-12
影响因子：
7.3
通讯作者：
Semenza GL
中科院分区：
文献类型：
--
作者：
Hubbi ME;Kshitiz;Gilkes DM;Rey S;Wong CC;Luo W;Kim DH;Dang CV;Levchenko A;Semenza GL
细胞周期阻滞是维持氧供需平衡的基本生理机制。缺氧诱导因子1（HIF-1）的转录活性介导了许多细胞对氧气供应减少的反应。我们报道了分离的HIF-1α亚基作为DNA复制抑制剂的作用，并且这种作用独立于HIF-1β和转录调节。缺氧时，HIF-1α与Cdc 6结合，并促进Cdc 6与MCM复合物之间的相互作用，Cdc 6是将具有DNA解旋酶活性的微小染色体维持（MCM）复合物装载到DNA上所必需的蛋白质。虽然Cdc 6和MCM复合物之间的相互作用增加了MCM蛋白与染色质的结合，但HIF-1α与复合物的结合减少了MCM复合物被激酶Cdc 7磷酸化和活化。因此，HIF-1α抑制复制起点的发射，减少DNA复制，并诱导各种细胞类型的细胞周期停滞。这些发现建立了一种转录非依赖性机制，通过该机制，HIF-1α的稳定导致细胞周期停滞以响应缺氧。
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.
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