Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Candidate for joint PhD degree from EMBL and Heidelberg University, Faculty of Biosciences, Heidelberg, Germany.
Nat Struct Mol Biol. 2021 Dec;28(12):997-1008. doi: 10.1038/s41594-021-00693-4. Epub 2021 Dec 9.
RNA polymerase I (Pol I) specifically synthesizes ribosomal RNA. Pol I upregulation is linked to cancer, while mutations in the Pol I machinery lead to developmental disorders. Here we report the cryo-EM structure of elongating human Pol I at 2.7 Å resolution. In the exit tunnel, we observe a double-stranded RNA helix that may support Pol I processivity. Our structure confirms that human Pol I consists of 13 subunits with only one subunit forming the Pol I stalk. Additionally, the structure of human Pol I in complex with the initiation factor RRN3 at 3.1 Å resolution reveals stalk flipping upon RRN3 binding. We also observe an inactivated state of human Pol I bound to an open DNA scaffold at 3.3 Å resolution. Lastly, the high-resolution structure of human Pol I allows mapping of disease-related mutations that can aid understanding of disease etiology.
RNA 聚合酶 I（Pol I）特异性合成核糖体 RNA。Pol I 的上调与癌症有关，而 Pol I 机制的突变会导致发育障碍。在这里，我们报告了 2.7 Å 分辨率下延伸状态的人源 Pol I 的 cryo-EM 结构。在出口隧道中，我们观察到一个双链 RNA 螺旋，它可能支持 Pol I 的持续性。我们的结构证实，人源 Pol I 由 13 个亚基组成，只有一个亚基形成 Pol I 柄。此外，我们还以 3.1 Å 的分辨率解析了人源 Pol I 与起始因子 RRN3 的复合物结构，揭示了 RRN3 结合后柄的翻转。我们还观察到 3.3 Å 分辨率下与开放 DNA 支架结合的失活状态的人源 Pol I。最后，人源 Pol I 的高分辨率结构可以映射与疾病相关的突变，有助于了解疾病的病因。
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