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

• Published in: Molecular cell 2023-07, Vol.83 (13), p.2258-2275.e11
• Main Authors: Townley, Brittany A., Buerer, Luke, Tsao, Ning, Bacolla, Albino, Mansoori, Fadhel, Rusanov, Timur, Clark, Nathanial, Goodarzi, Negar, Schmidt, Nicolas, Srivatsan, Sridhar Nonavinkere, Sun, Hua, Sample, Reilly A., Brickner, Joshua R., McDonald, Drew, Tsai, Miaw-Sheue, Walter, Matthew J., Wozniak, David F., Holehouse, Alex S., Pena, Vladimir, Tainer, John A., Fairbrother, William G., Mosammaparast, Nima
• Format: Article
• Language: English
• Subjects: Animals; DBR1; Introns - genetics; Mice; RNA lariat; RNA Nucleotidyltransferases - genetics; RNA processing; RNA Splicing; spliceosome; transcription; trichothiodystrophy; Trichothiodystrophy Syndromes - genetics
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2023.06.011

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. [Display omitted] •TTDN1 associates with DBR1 and promotes RNA lariat debranching in cells•TTDN1 links DBR1 to the intron-binding complex (IBC)•Loss of TTDN1 causes defects in splicing and in length-dependent gene expression•Ttdn1Δ/Δ mice recapitulate neurodevelopmental phenotypes of trichothiodystrophy Townley et al. demonstrate that TTDN1 is involved in RNA processing, linking the lariat debranching enzyme to a spliceosomal complex. This function of TTDN1 is shown to be critical for proper splicing and transcription, and Ttdn1 loss in mice leads to phenotypes seen in patients with trichothiodystrophy.