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

TY - JOUR

T1 - ALS-linked FUS mutants affect the localization of U7 snRNP and replication-dependent histone gene expression in human cells

AU - Gadgil, Ankur

AU - Walczak, Agnieszka

AU - Stępień, Agata

AU - Mechtersheimer, Jonas

AU - Nishimura, Agnes Lumi

AU - Shaw, Christopher E.

AU - Ruepp, Marc David

AU - Raczyńska, Katarzyna Dorota

N1 - Funding Information: The work of Ankur Gadgil, Agnieszka Walczak, Agata Stępień, and Katarzyna Dorota Raczyńska was funded by Polish National Science Centre (NCN) under the grant UMO-2016/21/B/NZ1/00232 to Katarzyna Dorota Raczyńska. The work of Jonas Mechtersheimer, Agnes Lumi Nishimura, Christopher E. Shaw, and Marc-David Ruepp is supported by the UK Dementia Research Institute, which receives its funding from UK DRI, Ltd., funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85107156195&partnerID=8YFLogxK

U2 - 10.1038/s41598-021-91453-3

DO - 10.1038/s41598-021-91453-3

M3 - Article

AN - SCOPUS:85107156195

SN - 2045-2322

VL - 11

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 11868

ER -