MED1磷酸化关联转录回收和肿瘤生长

Mammalian RNA polymerase II (Pol II) initiation, elongation, termination and reinitiation are well studied, but how Pol II dynamically recycles after the transcription cycle remains unclear. By establishing in vitro and in vivo transcription recycling systems, we find that human Mediator 1 (MED1), when phosphorylated at the mammal-specific threonine 1032 by cyclin-dependent kinase 9, dynamically travels with Pol II throughout the transcribed genes to drive Pol II recycling. Mechanistically, MED1 phosphorylation leads to an increase of recycled Pol II via the molecular bridge of MED31, enhancing mRNA output during the transcription recycling process. Importantly, MED1 phosphorylation increases during prostate cancer progression to the lethal phase, and pharmacological inhibition of CDK9 decreases prostate tumor growth through decreasing MED1 phosphorylation and Pol II recycling. Our findings reveal essential mechanisms underlying Pol II recycling and suggest a neglected, yet fundamental Pol II transcription process for therapeutic intervention.

哺乳动物RNA聚合酶II（RNA polymerase II, Pol II）的转录起始、延伸、终止与再起始过程已得到广泛研究，但转录周期完成后Pol II如何实现动态循环复用，目前仍有待阐明。本研究通过构建体外与体内转录循环复用系统，发现人类中介体亚基1（Mediator 1, MED1）在被细胞周期蛋白依赖性激酶9（cyclin-dependent kinase 9, CDK9）磷酸化哺乳动物特异性苏氨酸1032位点后，可与Pol II伴随沿转录基因动态移动，进而驱动Pol II的循环复用。从分子机制层面而言，MED1的磷酸化可通过MED31构成的分子桥梁，提升循环复用型Pol II的水平，进而增强转录循环复用过程中的mRNA合成量。值得关注的是，在前列腺癌进展至致死性阶段的过程中，MED1的磷酸化水平显著上调；而通过药理学手段抑制CDK9，可通过降低MED1磷酸化水平与Pol II循环复用效率，抑制前列腺肿瘤的生长。本研究揭示了Pol II循环复用的核心分子机制，并指出此前被忽视但至关重要的Pol II转录过程可作为治疗干预的潜在靶点。