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Structure of human RNA polymerase III elongation complex

Liang Li1 , Zishuo Yu1 , Dan Zhao1 , Yulei Ren1 , Haifeng Hou1,* , Yanhui Xu1,2,3,4,*

1Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College of Fudan University, Shanghai 200032, China
2The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology of China, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China
3Human Phenome Institute, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China
4State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010070, China
* Correspondence: Haifeng Hou(houhf@fudan.edu.cn)Yanhui Xu(xuyh@fudan.edu.cn)

RNA polymerase III (Pol III) transcribes essential structured small RNAs, such as tRNAs, 5S rRNA and U6 snRNA. The transcriptional activity of Pol III is tightly controlled and its dysregulation is associated with human diseases, such as cancer. Human Pol III has two isoforms with difference only in one of its subunits RPC7 (α and β). Despite structural studies of yeast Pol III, structure of human Pol III remains unsolved. Here, we determined the structures of 17-subunit human Pol IIIα complex in the backtracked and post-translocation states, respectively. Human Pol III contains a generally conserved catalytic core, similar to that of yeast counterpart, and structurally unique RPC3–RPC6–RPC7 heterotrimer and RPC10. The N-ribbon of TFIIS-like RPC10 docks on the RPC4–RPC5 heterodimer and the C-ribbon inserts into the funnel of Pol III in the backtracked state but is more flexible in the post-translocation state. RPC7 threads through the heterotrimer and bridges the stalk and Pol III core module. The winged helix 1 domain of RPC6 and the N-terminal region of RPC7α stabilize each other and may prevent Maf1-mediated repression of Pol III activity. The C-terminal FeS cluster of RPC6 coordinates a network of interactions that mediate core–heterotrimer contacts and stabilize Pol III. Our structural analysis sheds new light on the molecular mechanism of human Pol IIIα-specific transcriptional regulation and provides explanations for upregulated Pol III activity in RPC7α-dominant cancer cells.

https://doi.org/10.1038/s41422-021-00472-2

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