Sen1 architecture: RNA-DNA hybrid resolution, autoregulation, and insights into SETX inactivation in AOA2.
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| 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 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 (Sen1Hel) via an intrinsically disordered tether. In an autoinhibited state, the Sen1Sen1N domain regulates substrate engagement by promoting occlusion of the RNA substrate-binding cleft. The X-ray structure of an activated Sen1Hel engaging single-stranded RNA and ADP-SO4 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.
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| 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 |
| Journal | Molecular cell (Mol Cell) Vol. 83 Issue 20 Pg. 3692-3706.e5 (10 19 2023) ISSN: 1097-4164 [Electronic] United States |
| PMID | 37832548 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, U.S. Gov't, Non-P.H.S.) |
| Copyright | Published by Elsevier Inc. |
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