气候变化领域集成服务门户(CCPortal): The Clp1 R140H mutation alters tRNA metabolism and mRNA 3′ processing in mouse models of pontocerebellar hypoplasia

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DOI	10.1073/pnas.2110730118
	The Clp1 R140H mutation alters tRNA metabolism and mRNA 3′ processing in mouse models of pontocerebellar hypoplasia
	Monaghan C.E.; Adamson S.I.; Kapur M.; Chuang J.H.; Ackerman S.L.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:39
英文摘要	Homozygous mutation of the RNA kinase CLP1 (cleavage factor polyribonucleotide kinase subunit 1) causes pontocerebellar hypoplasia type 10 (PCH10), a pediatric neurodegenerative disease. CLP1 is associated with the transfer RNA (tRNA) splicing endonuclease complex and the cleavage and polyadenylation machinery, but its function remains unclear. We generated two mouse models of PCH10: one homozygous for the disease-associated Clp1 mutation, R140H, and one heterozygous for this mutation and a null allele. Both models exhibit loss of lower motor neurons and neurons of the deep cerebellar nuclei. To explore whether Clp1 mutation impacts tRNA splicing, we profiled the products of intron-containing tRNA genes. While mature tRNAs were expressed at normal levels in mutant mice, numerous other products of intron-containing tRNA genes were dysregulated, with pre-tRNAs, introns, and certain tRNA fragments up-regulated, and other fragments down-regulated. However, the spatiotemporal patterns of dysregulation do not correlate with pathogenicity for most altered tRNA products. To elucidate the effect of Clp1 mutation on precursor messenger RNA (pre-mRNA) cleavage, we analyzed poly(A) site (PAS) usage and gene expression in Clp1R140H/- spinal cord. PAS usage was shifted from proximal to distal sites in the mutant mouse, particularly in short and closely spaced genes. Many such genes were also expressed at lower levels in the Clp1R140H/- mouse, possibly as a result of impaired transcript maturation. These findings are consistent with the hypothesis that select genes are particularly dependent upon CLP1 for proper pre-mRNA cleavage, suggesting that impaired mRNA 3′ processing may contribute to pathogenesis in PCH10. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Alternative polyadenylation; Cleavage factor II; Deep cerebellar nuclei; Motor neuron degeneration; Trna splicing
语种	英语
scopus关键词	messenger RNA; Hexim1 protein, mouse; messenger RNA; RNA binding protein; RNA precursor; transcription factor; transfer RNA; 3' untranslated region; animal experiment; animal model; animal tissue; Article; cerebellum hypoplasia; cerebellum nucleus; Clp1 gene; controlled study; down regulation; female; gene; gene expression; gene mutation; motoneuron; mouse; nonhuman; pathogenesis; polyadenylation; RNA metabolism; upregulation; animal; C57BL mouse; cerebellum disease; degenerative disease; disease model; gene expression regulation; genetics; knockout mouse; male; metabolism; mutation; pathology; physiology; polyadenylation; RNA processing; Animals; Cerebellar Diseases; Disease Models, Animal; Female; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Neurodegenerative Diseases; Polyadenylation; RNA Precursors; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA, Transfer; RNA-Binding Proteins; Transcription Factors
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251008
作者单位	Department of Cellular and Molecular Medicine, Division of Biological Sciences, Section of Neurobiology, University of California San Diego, San Diego, CA 92093, United States; HHMI, University of California San Diego, San Diego, CA 92093, United States; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, United States; Department of Genetics and Genome Sciences, Institute for Systems Genomics, UConn Health, Farmington, CT 06030, United States
推荐引用方式 GB/T 7714	Monaghan C.E.,Adamson S.I.,Kapur M.,等. The Clp1 R140H mutation alters tRNA metabolism and mRNA 3′ processing in mouse models of pontocerebellar hypoplasia[J],2021,118(39).
APA	Monaghan C.E.,Adamson S.I.,Kapur M.,Chuang J.H.,&Ackerman S.L..(2021).The Clp1 R140H mutation alters tRNA metabolism and mRNA 3′ processing in mouse models of pontocerebellar hypoplasia.Proceedings of the National Academy of Sciences of the United States of America,118(39).
MLA	Monaghan C.E.,et al."The Clp1 R140H mutation alters tRNA metabolism and mRNA 3′ processing in mouse models of pontocerebellar hypoplasia".Proceedings of the National Academy of Sciences of the United States of America 118.39(2021).