A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy

Brittany A. Townley; Luke Buerer; Ning Tsao; Albino Bacolla; Fadhel Mansoori; Timur Rusanov; Nathanial Clark; Negar Goodarzi; Nicolas Schmidt; Sridhar Nonavinkere Srivatsan; Hua Sun; Reilly A. Sample; Joshua R. Brickner; Drew McDonald; Miaw Sheue Tsai; Matthew J. Walter; David F. Wozniak; Alex S. Holehouse; Vladimir Pena; John A. Tainer; William G. Fairbrother; Nima Mosammaparast

doi:10.1016/j.molcel.2023.06.011

A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy

Brittany A. Townley, Luke Buerer, Ning Tsao, Albino Bacolla, Fadhel Mansoori, Timur Rusanov, Nathanial Clark, Negar Goodarzi, Nicolas Schmidt, Sridhar Nonavinkere Srivatsan, Hua Sun, Reilly A. Sample, Joshua R. Brickner, Drew McDonald, Miaw Sheue Tsai, Matthew J. Walter, David F. Wozniak, Alex S. Holehouse, Vladimir Pena, John A. TainerWilliam G. Fairbrother, Nima Mosammaparast

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

The pre-mRNA life cycle requires intron processing; yet, how intron-processing defects influence splicing and gene expression is unclear. Here, we find that TTDN1/MPLKIP, which is encoded by a gene implicated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to spliceosomal function. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, whereas its N-terminal intrinsically disordered region (IDR) binds the intron-binding complex (IBC). TTDN1 loss, or a mutated IDR, causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. A Ttdn1-deficient mouse model recapitulates intron-processing defects and certain neurodevelopmental phenotypes seen in NP-TTD. Fusing DBR1 to the TTDN1 IDR is sufficient to recruit DBR1 to the IBC and circumvents the functional requirement for TTDN1. Collectively, our findings link RNA lariat processing with splicing outcomes by revealing the molecular function of TTDN1.

Original language	English
Pages (from-to)	2258-2275.e11
Journal	Molecular cell
Volume	83
Issue number	13
DOIs	https://doi.org/10.1016/j.molcel.2023.06.011
State	Published - Jul 6 2023

Keywords

DBR1
RNA lariat
RNA processing
spliceosome
transcription
trichothiodystrophy

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10.1016/j.molcel.2023.06.011

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Townley, B. A., Buerer, L., Tsao, N., Bacolla, A., Mansoori, F., Rusanov, T., Clark, N., Goodarzi, N., Schmidt, N., Srivatsan, S. N., Sun, H., Sample, R. A., Brickner, J. R., McDonald, D., Tsai, M. S., Walter, M. J., Wozniak, D. F., Holehouse, A. S., Pena, V., ... Mosammaparast, N. (2023). A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy. Molecular cell, 83(13), 2258-2275.e11. https://doi.org/10.1016/j.molcel.2023.06.011

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title = "A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy",

abstract = "The pre-mRNA life cycle requires intron processing; yet, how intron-processing defects influence splicing and gene expression is unclear. Here, we find that TTDN1/MPLKIP, which is encoded by a gene implicated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to spliceosomal function. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, whereas its N-terminal intrinsically disordered region (IDR) binds the intron-binding complex (IBC). TTDN1 loss, or a mutated IDR, causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. A Ttdn1-deficient mouse model recapitulates intron-processing defects and certain neurodevelopmental phenotypes seen in NP-TTD. Fusing DBR1 to the TTDN1 IDR is sufficient to recruit DBR1 to the IBC and circumvents the functional requirement for TTDN1. Collectively, our findings link RNA lariat processing with splicing outcomes by revealing the molecular function of TTDN1.",

keywords = "DBR1, RNA lariat, RNA processing, spliceosome, transcription, trichothiodystrophy",

author = "Townley, {Brittany A.} and Luke Buerer and Ning Tsao and Albino Bacolla and Fadhel Mansoori and Timur Rusanov and Nathanial Clark and Negar Goodarzi and Nicolas Schmidt and Srivatsan, {Sridhar Nonavinkere} and Hua Sun and Sample, {Reilly A.} and Brickner, {Joshua R.} and Drew McDonald and Tsai, {Miaw Sheue} and Walter, {Matthew J.} and Wozniak, {David F.} and Holehouse, {Alex S.} and Vladimir Pena and Tainer, {John A.} and Fairbrother, {William G.} and Nima Mosammaparast",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = jul,

day = "6",

doi = "10.1016/j.molcel.2023.06.011",

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Townley, BA, Buerer, L, Tsao, N, Bacolla, A, Mansoori, F, Rusanov, T, Clark, N, Goodarzi, N, Schmidt, N, Srivatsan, SN, Sun, H, Sample, RA, Brickner, JR, McDonald, D, Tsai, MS, Walter, MJ, Wozniak, DF, Holehouse, AS, Pena, V, Tainer, JA, Fairbrother, WG & Mosammaparast, N 2023, 'A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy', Molecular cell, vol. 83, no. 13, pp. 2258-2275.e11. https://doi.org/10.1016/j.molcel.2023.06.011

TY - JOUR

T1 - A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy

AU - Townley, Brittany A.

AU - Buerer, Luke

AU - Tsao, Ning

AU - Bacolla, Albino

AU - Mansoori, Fadhel

AU - Rusanov, Timur

AU - Clark, Nathanial

AU - Goodarzi, Negar

AU - Schmidt, Nicolas

AU - Srivatsan, Sridhar Nonavinkere

AU - Sun, Hua

AU - Sample, Reilly A.

AU - Brickner, Joshua R.

AU - McDonald, Drew

AU - Tsai, Miaw Sheue

AU - Walter, Matthew J.

AU - Wozniak, David F.

AU - Holehouse, Alex S.

AU - Pena, Vladimir

AU - Tainer, John A.

AU - Fairbrother, William G.

AU - Mosammaparast, Nima

PY - 2023/7/6

Y1 - 2023/7/6

N2 - The pre-mRNA life cycle requires intron processing; yet, how intron-processing defects influence splicing and gene expression is unclear. Here, we find that TTDN1/MPLKIP, which is encoded by a gene implicated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to spliceosomal function. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, whereas its N-terminal intrinsically disordered region (IDR) binds the intron-binding complex (IBC). TTDN1 loss, or a mutated IDR, causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. A Ttdn1-deficient mouse model recapitulates intron-processing defects and certain neurodevelopmental phenotypes seen in NP-TTD. Fusing DBR1 to the TTDN1 IDR is sufficient to recruit DBR1 to the IBC and circumvents the functional requirement for TTDN1. Collectively, our findings link RNA lariat processing with splicing outcomes by revealing the molecular function of TTDN1.

AB - The pre-mRNA life cycle requires intron processing; yet, how intron-processing defects influence splicing and gene expression is unclear. Here, we find that TTDN1/MPLKIP, which is encoded by a gene implicated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to spliceosomal function. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, whereas its N-terminal intrinsically disordered region (IDR) binds the intron-binding complex (IBC). TTDN1 loss, or a mutated IDR, causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells. A Ttdn1-deficient mouse model recapitulates intron-processing defects and certain neurodevelopmental phenotypes seen in NP-TTD. Fusing DBR1 to the TTDN1 IDR is sufficient to recruit DBR1 to the IBC and circumvents the functional requirement for TTDN1. Collectively, our findings link RNA lariat processing with splicing outcomes by revealing the molecular function of TTDN1.

KW - DBR1

KW - RNA lariat

KW - RNA processing

KW - spliceosome

KW - transcription

KW - trichothiodystrophy

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U2 - 10.1016/j.molcel.2023.06.011

DO - 10.1016/j.molcel.2023.06.011

M3 - Article

C2 - 37369199

AN - SCOPUS:85164260608

SN - 1097-2765

VL - 83

SP - 2258-2275.e11

JO - Molecular cell

JF - Molecular cell

IS - 13

ER -

A functional link between lariat debranching enzyme and the intron-binding complex is defective in non-photosensitive trichothiodystrophy

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