Characterization of the upstream and intron promoters of the gene encoding TAR DNA-binding protein

Abstract TAR DNA-binding protein (TDP-43, encoded by TARDBP) is a multifunctional protein that regulates transcription and RNA metabolism by binding DNA or RNA. TDP-43 has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) because abnormal accumulation of cleaved and phosphor...

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Autores principales:	Minami Hasegawa-Ogawa, Hirotaka James Okano
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/68b105c337854282abe302e98f6aae9a
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spelling	oai:doaj.org-article:68b105c337854282abe302e98f6aae9a2021-12-02T18:27:47ZCharacterization of the upstream and intron promoters of the gene encoding TAR DNA-binding protein10.1038/s41598-021-88015-y2045-2322https://doaj.org/article/68b105c337854282abe302e98f6aae9a2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88015-yhttps://doaj.org/toc/2045-2322Abstract TAR DNA-binding protein (TDP-43, encoded by TARDBP) is a multifunctional protein that regulates transcription and RNA metabolism by binding DNA or RNA. TDP-43 has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) because abnormal accumulation of cleaved and phosphorylated C-terminal fragments of TDP-43 in motor neurons is a pathological hallmark of ALS. Here, we cloned and analyzed the promoter region of the TARDBP gene. TARDBP upstream sequences and/or intron/luciferase constructs were generated, and their promoter activity was experimentally assessed. The upstream region predictably exhibited promoter activity and identified putative cis-acting elements, including the i-motif, was relevant for the regulation of TDP-43 expression. The cellular abundance of TDP-43 is strictly controlled, and its constancy is critically important for motor neuron survival. A machinery serving to maintain a constant level of TDP-43 is autoregulation via control of mRNA stability, a negative feedback system involving binding to the 3′ untranslated region of its own pre-mRNA. However, whether transcriptional mechanisms contribute to TDP-43 autoregulation is unclear. We further showed that TDP-43 negatively regulates the TARDBP promoter and, surprisingly, that disease-causing TDP-43 mutants lacked this regulatory activity. These results allowed the elucidation of a novel transcriptional autoregulatory mechanism of TDP-43.Minami Hasegawa-OgawaHirotaka James OkanoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Minami Hasegawa-Ogawa Hirotaka James Okano Characterization of the upstream and intron promoters of the gene encoding TAR DNA-binding protein
description	Abstract TAR DNA-binding protein (TDP-43, encoded by TARDBP) is a multifunctional protein that regulates transcription and RNA metabolism by binding DNA or RNA. TDP-43 has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) because abnormal accumulation of cleaved and phosphorylated C-terminal fragments of TDP-43 in motor neurons is a pathological hallmark of ALS. Here, we cloned and analyzed the promoter region of the TARDBP gene. TARDBP upstream sequences and/or intron/luciferase constructs were generated, and their promoter activity was experimentally assessed. The upstream region predictably exhibited promoter activity and identified putative cis-acting elements, including the i-motif, was relevant for the regulation of TDP-43 expression. The cellular abundance of TDP-43 is strictly controlled, and its constancy is critically important for motor neuron survival. A machinery serving to maintain a constant level of TDP-43 is autoregulation via control of mRNA stability, a negative feedback system involving binding to the 3′ untranslated region of its own pre-mRNA. However, whether transcriptional mechanisms contribute to TDP-43 autoregulation is unclear. We further showed that TDP-43 negatively regulates the TARDBP promoter and, surprisingly, that disease-causing TDP-43 mutants lacked this regulatory activity. These results allowed the elucidation of a novel transcriptional autoregulatory mechanism of TDP-43.
format	article
author	Minami Hasegawa-Ogawa Hirotaka James Okano
author_facet	Minami Hasegawa-Ogawa Hirotaka James Okano
author_sort	Minami Hasegawa-Ogawa
title	Characterization of the upstream and intron promoters of the gene encoding TAR DNA-binding protein
title_short	Characterization of the upstream and intron promoters of the gene encoding TAR DNA-binding protein
title_full	Characterization of the upstream and intron promoters of the gene encoding TAR DNA-binding protein
title_fullStr	Characterization of the upstream and intron promoters of the gene encoding TAR DNA-binding protein
title_full_unstemmed	Characterization of the upstream and intron promoters of the gene encoding TAR DNA-binding protein
title_sort	characterization of the upstream and intron promoters of the gene encoding tar dna-binding protein
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/68b105c337854282abe302e98f6aae9a
work_keys_str_mv	AT minamihasegawaogawa characterizationoftheupstreamandintronpromotersofthegeneencodingtardnabindingprotein AT hirotakajamesokano characterizationoftheupstreamandintronpromotersofthegeneencodingtardnabindingprotein
_version_	1718378043070742528

Characterization of the upstream and intron promoters of the gene encoding TAR DNA-binding protein

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