ALS-linked FUS mutants affect the localization of U7 snRNP and replication-dependent histone gene expression in human cells

Abstract Genes encoding replication-dependent histones lack introns, and the mRNAs produced are a unique class of RNA polymerase II transcripts in eukaryotic cells that do not end in a polyadenylated tail. Mature mRNAs are thus formed by a single endonucleolytic cleavage that releases the pre-mRNA f...

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Autores principales:	Ankur Gadgil, Agnieszka Walczak, Agata Stępień, Jonas Mechtersheimer, Agnes Lumi Nishimura, Christopher E. Shaw, Marc-David Ruepp, Katarzyna Dorota Raczyńska
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cc016ad4171f42469bc5c1df58514821
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spelling	oai:doaj.org-article:cc016ad4171f42469bc5c1df585148212021-12-02T18:25:05ZALS-linked FUS mutants affect the localization of U7 snRNP and replication-dependent histone gene expression in human cells10.1038/s41598-021-91453-32045-2322https://doaj.org/article/cc016ad4171f42469bc5c1df585148212021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91453-3https://doaj.org/toc/2045-2322Abstract Genes encoding replication-dependent histones lack introns, and the mRNAs produced are a unique class of RNA polymerase II transcripts in eukaryotic cells that do not end in a polyadenylated tail. Mature mRNAs are thus formed by a single endonucleolytic cleavage that releases the pre-mRNA from the DNA and is the only processing event necessary. U7 snRNP is one of the key factors that determines the cleavage site within the 3ʹUTR of replication-dependent histone pre-mRNAs. We have previously showed that the FUS protein interacts with U7 snRNA/snRNP and regulates the expression of histone genes by stimulating transcription and 3ʹ end maturation. Mutations in the FUS gene first identified in patients with amyotrophic lateral sclerosis (ALS) lead to the accumulation of the FUS protein in cytoplasmic inclusions. Here, we report that mutations in FUS lead to disruption of the transcriptional activity of FUS and mislocalization of U7 snRNA/snRNP in cytoplasmic aggregates in cellular models and primary neurons. As a consequence, decreased transcriptional efficiency and aberrant 3ʹ end processing of histone pre-mRNAs were observed. This study highlights for the first time the deregulation of replication-dependent histone gene expression and its involvement in ALS.Ankur GadgilAgnieszka WalczakAgata StępieńJonas MechtersheimerAgnes Lumi NishimuraChristopher E. ShawMarc-David RueppKatarzyna Dorota RaczyńskaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ankur Gadgil Agnieszka Walczak Agata Stępień Jonas Mechtersheimer Agnes Lumi Nishimura Christopher E. Shaw Marc-David Ruepp Katarzyna Dorota Raczyńska ALS-linked FUS mutants affect the localization of U7 snRNP and replication-dependent histone gene expression in human cells
description	Abstract Genes encoding replication-dependent histones lack introns, and the mRNAs produced are a unique class of RNA polymerase II transcripts in eukaryotic cells that do not end in a polyadenylated tail. Mature mRNAs are thus formed by a single endonucleolytic cleavage that releases the pre-mRNA from the DNA and is the only processing event necessary. U7 snRNP is one of the key factors that determines the cleavage site within the 3ʹUTR of replication-dependent histone pre-mRNAs. We have previously showed that the FUS protein interacts with U7 snRNA/snRNP and regulates the expression of histone genes by stimulating transcription and 3ʹ end maturation. Mutations in the FUS gene first identified in patients with amyotrophic lateral sclerosis (ALS) lead to the accumulation of the FUS protein in cytoplasmic inclusions. Here, we report that mutations in FUS lead to disruption of the transcriptional activity of FUS and mislocalization of U7 snRNA/snRNP in cytoplasmic aggregates in cellular models and primary neurons. As a consequence, decreased transcriptional efficiency and aberrant 3ʹ end processing of histone pre-mRNAs were observed. This study highlights for the first time the deregulation of replication-dependent histone gene expression and its involvement in ALS.
format	article
author	Ankur Gadgil Agnieszka Walczak Agata Stępień Jonas Mechtersheimer Agnes Lumi Nishimura Christopher E. Shaw Marc-David Ruepp Katarzyna Dorota Raczyńska
author_facet	Ankur Gadgil Agnieszka Walczak Agata Stępień Jonas Mechtersheimer Agnes Lumi Nishimura Christopher E. Shaw Marc-David Ruepp Katarzyna Dorota Raczyńska
author_sort	Ankur Gadgil
title	ALS-linked FUS mutants affect the localization of U7 snRNP and replication-dependent histone gene expression in human cells
title_short	ALS-linked FUS mutants affect the localization of U7 snRNP and replication-dependent histone gene expression in human cells
title_full	ALS-linked FUS mutants affect the localization of U7 snRNP and replication-dependent histone gene expression in human cells
title_fullStr	ALS-linked FUS mutants affect the localization of U7 snRNP and replication-dependent histone gene expression in human cells
title_full_unstemmed	ALS-linked FUS mutants affect the localization of U7 snRNP and replication-dependent histone gene expression in human cells
title_sort	als-linked fus mutants affect the localization of u7 snrnp and replication-dependent histone gene expression in human cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/cc016ad4171f42469bc5c1df58514821
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ALS-linked FUS mutants affect the localization of U7 snRNP and replication-dependent histone gene expression in human cells

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