A CDK11-dependent RNA polymerase II pause-checkpoint precedes CDK9-mediated transition to transcriptional elongation

Controlled gene expression is achieved through the intricate regulation of Pol II progression through transcription-cycle checkpoints. While the contribution of CDK9 for Pol II pause-release is well established, the requirement for other CDKs has not been fully elucidated. Here we propose a new role for CDK11 in the Pol II pausing-to-elongation transition at a checkpoint that precedes and is independent from CDK9. Selective CDK11 inhibition or degradation results in acute ablation of RNA synthesis near the beginning of transcriptional units and genome-wide stalling of Pol II at TSS-proximal-regions. High-resolution chromatin-immunoprecipitation and precision-nuclear-run-on assays reveals spatial differences between CDK11- and CDK9-dependent Pol II pause sites, with CDK11 regulating Pol II upstream of the CDK9 checkpoint within the pausing zone. Cancer cells exhibit profound reliance on CDK11, with CDK11 inhibition reducing tumour burden in in vivo models of blood cancer, demonstrating the importance of CDK11-dependent Pol II regulation for aggressive haematological malignancies.

受控基因表达的实现，依赖于对RNA聚合酶II（Pol II）在转录周期检查点处的进程进行精密调控。尽管细胞周期蛋白依赖性激酶9（CDK9）在Pol II暂停释放中的作用已得到充分证实，但其他CDK家族激酶的功能仍未完全阐明。本研究揭示了细胞周期蛋白依赖性激酶11（CDK11）的全新功能：其可在一个早于且不依赖于CDK9的检查点处，调控Pol II从暂停状态向延伸状态的转变。选择性抑制或降解CDK11，会导致转录单元起始区域附近的RNA合成急剧受阻，并使全基因组范围内的Pol II在转录起始位点（TSS）近端区域停滞。高分辨率染色质免疫沉淀（chromatin-immunoprecipitation）与精准核run-on实验揭示了依赖CDK11与依赖CDK9的Pol II暂停位点之间的空间差异：CDK11在暂停区域内调控CDK9检查点上游的Pol II进程。癌细胞对CDK11表现出极强的依赖性，抑制CDK11可降低血液癌症体内模型的肿瘤负荷，这证实了依赖CDK11的Pol II调控在侵袭性血液恶性肿瘤中的重要性。