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: | , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/68b105c337854282abe302e98f6aae9a |
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| Sumario: | 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. |
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