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A condensate forming tether for lariat debranching enzyme is defective in non-photosensitive trichothiodystrophy

Brittany A. Townley, Luke Buerer, Albino Bacolla, Timur Rusanov, Nicolas Schmidt, Sridhar N. Srivatsan, Nathanial E. Clark, Fadhel Mansoori, Reilly A. Sample, Joshua R. Brickner, Drew McDonald, Miaw-Sheue Tsai, Matthew J. Walter, David F. Wozniak, Alex S. Holehouse, John A. Tainer, William G. Fairbrother, View ORCID ProfileNima Mosammaparast
doi: https://doi.org/10.1101/2022.11.03.515106
Brittany A. Townley
1Department of Pathology & Immunology, Center for Genome Integrity, Washington University School of Medicine, St. Louis, MO 63110, USA
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Luke Buerer
2Center for Computational Molecular Biology, Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI 02912, USA
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Albino Bacolla
3Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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Timur Rusanov
1Department of Pathology & Immunology, Center for Genome Integrity, Washington University School of Medicine, St. Louis, MO 63110, USA
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Nicolas Schmidt
1Department of Pathology & Immunology, Center for Genome Integrity, Washington University School of Medicine, St. Louis, MO 63110, USA
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Sridhar N. Srivatsan
4Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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Nathanial E. Clark
2Center for Computational Molecular Biology, Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI 02912, USA
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Fadhel Mansoori
1Department of Pathology & Immunology, Center for Genome Integrity, Washington University School of Medicine, St. Louis, MO 63110, USA
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Reilly A. Sample
1Department of Pathology & Immunology, Center for Genome Integrity, Washington University School of Medicine, St. Louis, MO 63110, USA
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Joshua R. Brickner
1Department of Pathology & Immunology, Center for Genome Integrity, Washington University School of Medicine, St. Louis, MO 63110, USA
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Drew McDonald
5Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
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Miaw-Sheue Tsai
5Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
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Matthew J. Walter
4Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
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David F. Wozniak
6Department of Psychiatry, Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110-1093, USA
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Alex S. Holehouse
7Department of Biochemistry & Molecular Biophysics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA
8Center for Science and Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO 63130, USA
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John A. Tainer
3Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
9Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
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William G. Fairbrother
2Center for Computational Molecular Biology, Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI 02912, USA
10Hassenfeld Child Health Innovation Institute of Brown University, Providence, RI 02912, USA
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  • For correspondence: nima@wustl.edu william_fairbrother@brown.edu
Nima Mosammaparast
1Department of Pathology & Immunology, Center for Genome Integrity, Washington University School of Medicine, St. Louis, MO 63110, USA
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  • ORCID record for Nima Mosammaparast
  • For correspondence: nima@wustl.edu william_fairbrother@brown.edu
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Summary

The pre-mRNA life cycle requires intron processing; yet, how intron processing defects influence splicing and gene expression is unclear. Here, we find TTDN1, which is frequently mutated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to the spliceosome. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, while its N-terminal intrinsically disordered region (IDR) binds the intron binding complex (IBC). The IDR forms condensates in vitro and is needed for IBC interaction. TTDN1 loss causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. Ttdn1Δ/Δ mice recapitulate intron processing defects and neurodevelopmental phenotypes seen in NP-TTD. A DBR1-IDR fusion recruits DBR1 to the IBC and circumvents the requirement for TTDN1, indicating this tethering role as its major molecular function. Collectively, our findings unveil key functional connections between lariat processing, splicing outcomes, and NP-TTD molecular pathology.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 04, 2022.
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A condensate forming tether for lariat debranching enzyme is defective in non-photosensitive trichothiodystrophy
Brittany A. Townley, Luke Buerer, Albino Bacolla, Timur Rusanov, Nicolas Schmidt, Sridhar N. Srivatsan, Nathanial E. Clark, Fadhel Mansoori, Reilly A. Sample, Joshua R. Brickner, Drew McDonald, Miaw-Sheue Tsai, Matthew J. Walter, David F. Wozniak, Alex S. Holehouse, John A. Tainer, William G. Fairbrother, Nima Mosammaparast
bioRxiv 2022.11.03.515106; doi: https://doi.org/10.1101/2022.11.03.515106
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A condensate forming tether for lariat debranching enzyme is defective in non-photosensitive trichothiodystrophy
Brittany A. Townley, Luke Buerer, Albino Bacolla, Timur Rusanov, Nicolas Schmidt, Sridhar N. Srivatsan, Nathanial E. Clark, Fadhel Mansoori, Reilly A. Sample, Joshua R. Brickner, Drew McDonald, Miaw-Sheue Tsai, Matthew J. Walter, David F. Wozniak, Alex S. Holehouse, John A. Tainer, William G. Fairbrother, Nima Mosammaparast
bioRxiv 2022.11.03.515106; doi: https://doi.org/10.1101/2022.11.03.515106

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