Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor

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Authors

HAŠANOVÁ Zdenka KLÁPŠŤOVÁ Veronika PORRUA Odil ŠTEFL Richard ŠEBESTA Marek

Year of publication 2023
Type Article in Periodical
Magazine / Source Nucleic Acids Research
MU Faculty or unit

Central European Institute of Technology

Citation
Web https://doi.org/10.1093/nar/gkad092
Doi http://dx.doi.org/10.1093/nar/gkad092
Keywords RNA-POLYMERASE-II; OCULOMOTOR APRAXIA TYPE-2; SACCHAROMYCES-CEREVISIAE SEN1; GENOME INSTABILITY; REPLICATION CONFLICTS; RNA/DNA HYBRIDS; PAUSE SITES; INFO-RNA; HELICASE; ATAXIA
Description 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.
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