Cryo-EM structures of human RNA polymerase I
Agata D Misiaszek1,2, Mathias Girbig1,2, Helga Grötsch1
1Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
Nature Structural & Molecular Biology
|December 10, 2021
Summary
We determined the structure of human RNA polymerase I (Pol I), revealing a double-stranded RNA helix that may enhance processivity. This structural insight into Pol I function aids understanding of cancer and developmental disorders.
Area of Science:
- Molecular Biology
- Structural Biology
- Biochemistry
Background:
- RNA polymerase I (Pol I) is crucial for synthesizing ribosomal RNA.
- Pol I dysregulation is implicated in cancer and developmental disorders.
- Understanding Pol I structure is key to deciphering its function and disease links.
Purpose of the Study:
- To determine the high-resolution cryo-EM structure of elongating human Pol I.
- To investigate the structural basis of Pol I processivity and regulation.
- To map disease-associated mutations onto the Pol I structure.
Main Methods:
- Cryo-electron microscopy (cryo-EM) at resolutions up to 2.7 Å.
- Structural analysis of human Pol I in different functional states.
- Biochemical and structural characterization of Pol I-RRN3 complex.
Main Results:
- A double-stranded RNA helix was observed in the Pol I exit tunnel, potentially aiding processivity.
- Human Pol I comprises 13 subunits, with a single subunit forming the Pol I stalk.
- RRN3 binding induces stalk flipping in Pol I.
- Structures of inactivated Pol I bound to DNA and Pol I-RRN3 complex were resolved.
Conclusions:
- The high-resolution structures provide unprecedented insights into human Pol I function and regulation.
- Structural findings offer a basis for understanding disease mechanisms linked to Pol I mutations.
- This work lays the foundation for future therapeutic strategies targeting Pol I.
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