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• W3193779074 abstract "Abstract Nuclear clearance of the DNA/RNA-binding protein TDP-43 is a pathologic hallmark of amyotrophic lateral sclerosis and frontotemporal dementia that remains unexplained. Moreover, our current understanding of TDP-43 nucleocytoplasmic shuttling does not fully explain the predominantly nuclear localization of TDP-43 in healthy cells. Here, we used permeabilized and live-cell models to investigate TDP-43 nuclear export and the role of RNA in TDP-43 localization. We show that TDP-43 nuclear efflux occurs in low-ATP conditions and independent of active mRNA export, consistent with export by passive diffusion through nuclear pore channels. TDP-43 nuclear residence requires binding to GU-rich nuclear intronic pre-mRNAs, based on the induction of TDP-43 nuclear efflux by RNase and GU-rich oligomers and TDP-43 nuclear retention conferred by pre-mRNA splicing inhibitors. Mutation of TDP-43 RNA recognition motifs disrupts TDP-43 nuclear accumulation and abolishes transcriptional blockade-induced TDP-43 nuclear efflux, demonstrating strict dependence of TDP-43 nuclear localization on RNA binding. Thus, the nuclear abundance of GU-rich intronic pre-mRNAs, as dictated by the balance of transcription and pre-mRNA processing, regulates TDP-43 nuclear sequestration and availability for passive nuclear export." @default.
• W3193779074 created "2021-08-30" @default.
• W3193779074 creator A5026827614 @default.
• W3193779074 creator A5045095567 @default.
• W3193779074 creator A5045098375 @default.
• W3193779074 creator A5051391629 @default.
• W3193779074 creator A5060353683 @default.
• W3193779074 creator A5060802168 @default.
• W3193779074 creator A5067631956 @default.
• W3193779074 date "2021-08-24" @default.
• W3193779074 modified "2023-10-16" @default.
• W3193779074 title "Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export" @default.
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