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-Structure paper
Title | Sen1 architecture: RNA-DNA hybrid resolution, autoregulation, and insights into SETX inactivation in AOA2. |
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Journal, issue, pages | Mol Cell, Vol. 83, Issue 20, Page 3692-33706.e5, Year 2023 |
Publish date | Oct 19, 2023 |
Authors | C Denise Appel / Oya Bermek / Venkata P Dandey / Makayla Wood / Elizabeth Viverette / Jason G Williams / Jonathan Bouvette / Amanda A Riccio / Juno M Krahn / Mario J Borgnia / R Scott Williams / |
PubMed Abstract | The senataxin (SETX, Sen1 in yeasts) RNA-DNA hybrid resolving helicase regulates multiple nuclear transactions, including DNA replication, transcription, and DNA repair, but the molecular basis for ...The senataxin (SETX, Sen1 in yeasts) RNA-DNA hybrid resolving helicase regulates multiple nuclear transactions, including DNA replication, transcription, and DNA repair, but the molecular basis for Sen1 activities is ill defined. Here, Sen1 cryoelectron microscopy (cryo-EM) reconstructions reveal an elongated inchworm-like architecture. Sen1 is composed of an amino terminal helical repeat Sen1 N-terminal (Sen1N) regulatory domain that is flexibly linked to its C-terminal SF1B helicase motor core (Sen1) via an intrinsically disordered tether. In an autoinhibited state, the Sen1 domain regulates substrate engagement by promoting occlusion of the RNA substrate-binding cleft. The X-ray structure of an activated Sen1 engaging single-stranded RNA and ADP-SO shows that the enzyme encircles RNA and implicates a single-nucleotide power stroke in the Sen1 RNA translocation mechanism. Together, our data unveil dynamic protein-protein and protein-RNA interfaces underpinning helicase regulation and inactivation of human SETX activity by RNA-binding-deficient mutants in ataxia with oculomotor apraxia 2 neurodegenerative disease. |
External links | Mol Cell / PubMed:37832548 / PubMed Central |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 3.01 - 4.56 Å |
Structure data | EMDB-29426, PDB-8fth: EMDB-29439, PDB-8ftk: EMDB-29440: SETX-Sen1N domain PDB-8ftm: |
Chemicals | ChemComp-ADP: ChemComp-SO4: ChemComp-HOH: |
Source |
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Keywords | TRANSCRIPTION / Helicase / DNA repair / RNA-DNA hybrid / TRANSCRIPTION/RNA / TRANSCRIPTION-RNA complex |