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The activity of the transcription factor hypoxia-inducible factor 1α (HIF-1α) is increased in response to reduced intracellular oxygen. Enzymes of the protein ubiquitin machinery that signal the destruction or stabilization of HIF-1α tightly control this transcriptional response. Here, we show that muscle A kinase–anchoring protein (mAKAP) organized ubiquitin E3 ligases that managed the stability of HIF-1α and optimally positioned it close to its site of action inside the nucleus. Functional experiments in cardiomyocytes showed that depletion of mAKAP or disruption of its targeting to the perinuclear region altered the stability of HIF-1α and transcriptional activation of genes associated with hypoxia. Thus, we propose that compartmentalization of oxygen-sensitive signaling components may influence the fidelity and magnitude of the hypoxic response.