【摘 要】
：
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
【机 构】
：
Fudan University Shanghai Cancer Center,Institutes of Biomedical Sciences,State Key Laboratory of Ge
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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 PolⅢ 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 RPC7cα 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.
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