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Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor.
Hasanova, Zdenka; Klapstova, Veronika; Porrua, Odil; Stefl, Richard; Sebesta, Marek.
Afiliação
  • Hasanova Z; CEITEC-Central European Institute of Technology, Masaryk University, Brno CZ-62500, Czechia.
  • Klapstova V; CEITEC-Central European Institute of Technology, Masaryk University, Brno CZ-62500, Czechia.
  • Porrua O; National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno CZ-62500, Czechia.
  • Stefl R; Université Paris Cité, CNRS, Institut Jacques Monod, F-75013 Paris, France.
  • Sebesta M; Institut de Génétique Moléculaire de Montpellier, Univ Montpellier, CNRS, Montpellier, France.
Nucleic Acids Res ; 51(6): 2818-2837, 2023 04 11.
Article em En | MEDLINE | ID: mdl-36864660
Prolonged pausing of the transcription machinery may lead to the formation of three-stranded nucleic acid structures, called R-loops, typically resulting from the annealing of the nascent RNA with the template DNA. Unscheduled persistence of R-loops and RNA polymerases may interfere with transcription itself and other essential processes such as DNA replication and repair. Senataxin (SETX) is a putative helicase, mutated in two neurodegenerative disorders, which has been implicated in the control of R-loop accumulation and in transcription termination. However, understanding the precise role of SETX in these processes has been precluded by the absence of a direct characterisation of SETX biochemical activities. Here, we purify and characterise the helicase domain of SETX in parallel with its yeast orthologue, Sen1. Importantly, we show that SETX is a bona fide helicase with the ability to resolve R-loops. Furthermore, SETX has retained the transcription termination activity of Sen1 but functions in a species-specific manner. Finally, subsequent characterisation of two SETX variants harbouring disease-associated mutations shed light into the effect of such mutations on SETX folding and biochemical properties. Altogether, these results broaden our understanding of SETX function in gene expression and the maintenance of genome integrity and provide clues to elucidate the molecular basis of SETX-associated neurodegenerative diseases.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: DNA Helicases / RNA Helicases / Terminação da Transcrição Genética Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: DNA Helicases / RNA Helicases / Terminação da Transcrição Genética Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article