@article{df62ae0db35841408db39d3701c806aa,
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 = "Funding Information: We thank Zhongsheng You, Hani Zaher, Chaorui Duan, Harrison Gabel, and Diana Christian for suggestions during the course of these studies. We thank John Schultz (UC Davis) for amino acid analysis; Ross Tomaino (Harvard Medical School Taplin Core) for proteomics, the Genome Technology Access Center (GTAC), and the Genome Engineering and iPSC (GEiC) Center at Washington University; and the Nascent Transcriptomics Core (Harvard Medical School) for performing PRO-seq library construction and for assistance with data analysis. We acknowledge the Extreme Science and Engineering Discovery Environment (XSEDE, PSC allocations TG-BIO160040 and TG-MCB170053), which is supported by NSF grant ACI-1548562 , and the Texas Advanced Computing Center (TACC, http://www.tacc.utexas.edu ) at The University of Texas at Austin for providing HPC resources. This work was supported by the NIH ( F31 CA0254143 to B.A.T., R35 CA220430 to J.A.T., R01 GM105681 and R01 GM127472 to W.G.F., R01 CA193318 to N.M., and P01 CA092584 to J.A.T. and N.M.), the Wellcome Trust ( 220300Z/20/Z to V.P.), the Edward P. Evans Foundation (M.J.W.), the Foundation for Barnes-Jewish Hospital Cancer Frontier Fund (M.J.W.), an American Cancer Society Research Scholar award ( RSG-18-156-01-DMC to N.M.), the Barnard Foundation (N.M.), Centene Corporation (N.M.), and the Siteman Cancer Center (N.M. and M.J.W.). J.A.T. is also supported by Cancer Prevention Research Institute of Texas (CPRIT) grant RP180813 and the Robert A. Welch Chemistry Chair . A.S.H. is supported by a Longer Life Foundation grant (a collaboration between RGA and Washington University). Partial support for the mouse behavioral studies was provided by the Intellectual and Developmental Disabilities Research Center at the Washington University School of Medicine (P50 HD10342 to D.F.W.). Funding Information: We thank Zhongsheng You, Hani Zaher, Chaorui Duan, Harrison Gabel, and Diana Christian for suggestions during the course of these studies. We thank John Schultz (UC Davis) for amino acid analysis; Ross Tomaino (Harvard Medical School Taplin Core) for proteomics, the Genome Technology Access Center (GTAC), and the Genome Engineering and iPSC (GEiC) Center at Washington University; and the Nascent Transcriptomics Core (Harvard Medical School) for performing PRO-seq library construction and for assistance with data analysis. We acknowledge the Extreme Science and Engineering Discovery Environment (XSEDE, PSC allocations TG-BIO160040 and TG-MCB170053), which is supported by NSF grant ACI-1548562, and the Texas Advanced Computing Center (TACC, http://www.tacc.utexas.edu) at The University of Texas at Austin for providing HPC resources. This work was supported by the NIH (F31 CA0254143 to B.A.T. R35 CA220430 to J.A.T. R01 GM105681 and R01 GM127472 to W.G.F. R01 CA193318 to N.M. and P01 CA092584 to J.A.T. and N.M.), the Wellcome Trust (220300Z/20/Z to V.P.), the Edward P. Evans Foundation (M.J.W.), the Foundation for Barnes-Jewish Hospital Cancer Frontier Fund (M.J.W.), an American Cancer Society Research Scholar award (RSG-18-156-01-DMC to N.M.), the Barnard Foundation (N.M.), Centene Corporation (N.M.), and the Siteman Cancer Center (N.M. and M.J.W.). J.A.T. is also supported by Cancer Prevention Research Institute of Texas (CPRIT) grant RP180813 and the Robert A. Welch Chemistry Chair. A.S.H. is supported by a Longer Life Foundation grant (a collaboration between RGA and Washington University). Partial support for the mouse behavioral studies was provided by the Intellectual and Developmental Disabilities Research Center at the Washington University School of Medicine (P50 HD10342 to D.F.W.). B.A.T. N.T. F.M. N.C. T.R. N.S. R.A.S. J.R.B. D.M. M.-S.T. and N.M. carried out cellular, biochemical, and animal experiments. B.A.T. L.B. A.B. S.N.S. and H.S. carried out bioinformatic analysis. N.G. purified the IBC. D.F.W. analyzed mouse behavioral studies. A.S.H. performed computer simulations. M.J.W. supervised S.N.S. V.P. supervised N.G. J.A.T. supervised A.B. W.G.F. supervised L.B. and N.C. N.M. supervised the project and wrote the manuscript with B.A.T. and N.T. with input from all other authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. We worked to ensure sex balance in the selection of non-human subjects. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",
year = "2023",
month = jul,
day = "6",
doi = "10.1016/j.molcel.2023.06.011",
language = "English",
volume = "83",
pages = "2258--2275.e11",
journal = "Molecular cell",
issn = "1097-2765",
number = "13",
}