Suppression of premature transcription termination leads to reduced mRNA isoform diversity and neurodegeneration.

Autor:	LaForce GR; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA., Farr JS; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA., Liu J; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA., Akesson C; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA., Gumus E; Department of Medical Genetics, Faculty of Medicine, Mugla Sitki Kocman University, Mugla 48000, Turkey; Department of Medical Genetics, Faculty of Medicine, University of Harran, Sanliurfa 63000, Turkey., Pinkard O; Department of Molecular Biology and Genetics, Johns Hopkins, Baltimore, MD 21205, USA., Miranda HC; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA., Johnson K; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA., Sweet TJ; Department of Molecular Biology and Genetics, Johns Hopkins, Baltimore, MD 21205, USA., Ji P; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA., Lin A; Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, WC67+HC Dongcheng, Beijing, China., Coller J; Department of Molecular Biology and Genetics, Johns Hopkins, Baltimore, MD 21205, USA., Philippidou P; Department of Neurosciences, Case Western Reserve University, Cleveland, OH 44106, USA., Wagner EJ; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA; Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA., Schaffer AE; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: ashleigh.schaffer@case.edu.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2022 Apr 20; Vol. 110 (8), pp. 1340-1357.e7. Date of Electronic Publication: 2022 Feb 08.
DOI:	10.1016/j.neuron.2022.01.018
Abstrakt:	Tight regulation of mRNA isoform expression is essential for neuronal development, maintenance, and function; however, the repertoire of proteins that govern isoform composition and abundance remains incomplete. Here, we show that the RNA kinase CLP1 regulates mRNA isoform expression through suppression of proximal cleavage and polyadenylation. We found that human stem-cell-derived motor neurons without CLP1 or with the disease-associated CLP1 p.R140H variant had distinct patterns of RNA-polymerase-II-associated cleavage and polyadenylation complex proteins that correlated with polyadenylation site usage. These changes resulted in imbalanced mRNA isoform expression of long genes important for neuronal function that were recapitulated in vivo. Strikingly, we observed the same pattern of reduced mRNA isoform diversity in 3' end sequencing data from brain tissues of patients with neurodegenerative disease. Together, our results identify a previously uncharacterized role for CLP1 in mRNA 3' end formation and reveal an mRNA misprocessing signature in neurodegeneration that may suggest a common mechanism of disease. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu