Extended DNA threading through a dual-engine motor module of the activating signal co-integrator 1 complex

Junqiao Jia, Tarek Hilal, Katherine E. Bohnsack, Aleksandar Chernev, Ning Tsao, Juliane Bethmann, Aruna Arumugam, Lane Parmely, Nicole Holton, Bernhard Loll, Nima Mosammaparast, Markus T. Bohnsack, Henning Urlaub and Markus C. Wahl ()
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Junqiao Jia: Laboratory of Structural Biochemistry
Tarek Hilal: Laboratory of Structural Biochemistry
Katherine E. Bohnsack: Universitätsmedizin Göttingen, Department of Molecular Biology
Aleksandar Chernev: Bioanalytical Mass Spectrometry
Ning Tsao: Washington University School of Medicine, Department of Pathology & Immunology and Center for Genome Integrity
Juliane Bethmann: Bioanalytical Mass Spectrometry
Aruna Arumugam: Laboratory of Structural Biochemistry
Lane Parmely: Washington University School of Medicine, Department of Pathology & Immunology and Center for Genome Integrity
Nicole Holton: Laboratory of Structural Biochemistry
Bernhard Loll: Laboratory of Structural Biochemistry
Nima Mosammaparast: Washington University School of Medicine, Department of Pathology & Immunology and Center for Genome Integrity
Markus T. Bohnsack: Universitätsmedizin Göttingen, Department of Molecular Biology
Henning Urlaub: Bioanalytical Mass Spectrometry
Markus C. Wahl: Laboratory of Structural Biochemistry

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Activating signal co-integrator 1 complex (ASCC) subunit 3 (ASCC3) supports diverse genome maintenance and gene expression processes, and contains tandem Ski2-like NTPase/helicase cassettes crucial for these functions. Presently, the molecular mechanisms underlying ASCC3 helicase activity and regulation remain unresolved. We present cryogenic electron microscopy, DNA-protein cross-linking/mass spectrometry as well as in vitro and cellular functional analyses of the ASCC3-TRIP4 sub-module of ASCC. Unlike the related spliceosomal SNRNP200 RNA helicase, ASCC3 can thread substrates through both helicase cassettes. TRIP4 docks on ASCC3 via a zinc finger domain and stimulates the helicase by positioning an ASC-1 homology domain next to the C-terminal helicase cassette of ASCC3, likely supporting substrate engagement and assisting the DNA exit. TRIP4 binds ASCC3 mutually exclusively with the DNA/RNA dealkylase, ALKBH3, directing ASCC3 for specific processes. Our findings define ASCC3-TRIP4 as a tunable motor module of ASCC that encompasses two cooperating NTPase/helicase units functionally expanded by TRIP4.

Date: 2023
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DOI: 10.1038/s41467-023-37528-3

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