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

J 2023

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

HAŠANOVÁ, Zdenka, Veronika KLÁPŠŤOVÁ, Odil PORRUA, Richard ŠTEFL, Marek ŠEBESTA et. al.

Základní údaje

Originální název

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

Autoři

HAŠANOVÁ, Zdenka (703 Slovensko, domácí), Veronika KLÁPŠŤOVÁ (203 Česká republika, domácí), Odil PORRUA, Richard ŠTEFL (203 Česká republika, garant, domácí) a Marek ŠEBESTA (703 Slovensko, domácí)

Vydání

Nucleic Acids Research, Oxford University Press, 2023, 0305-1048

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 14.900 v roce 2022

Kód RIV

RIV/00216224:14740/23:00132763

Organizační jednotka

Středoevropský technologický institut

DOI

http://dx.doi.org/10.1093/nar/gkad092

UT WoS

000942750600001

Klíčová slova anglicky

RNA-POLYMERASE-II; OCULOMOTOR APRAXIA TYPE-2; SACCHAROMYCES-CEREVISIAE SEN1; GENOME INSTABILITY; REPLICATION CONFLICTS; RNA/DNA HYBRIDS; PAUSE SITES; INFO-RNA; HELICASE; ATAXIA

Štítky

CF BIC, CF PROT, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 17. 10. 2024 13:47, Ing. Marie Švancarová

Anotace

V originále

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.

Návaznosti

EF18_046/0015974, projekt VaV

Název: Modernizace České infrastruktury pro integrativní strukturní biologii

GM21-10464M, projekt VaV

Název: Strukturní charakterizace interakcí mezi transkripcí a opravou DNA

Investor: Grantová agentura ČR, Structural characterisation of the interplay between transcription and DNA repair

649030, interní kód MU

Název: DECOR - Dynamic assembly and exchange of RNA polymerase II CTD factors (Akronym: DECOR)

Investor: Evropská unie, DECOR - Dynamic assembly and exchange of RNA polymerase II CTD factors, ERC (Excellent Science)

90127, velká výzkumná infrastruktura

Název: CIISB II

Citovat

HAŠANOVÁ, Zdenka, Veronika KLÁPŠŤOVÁ, Odil PORRUA, Richard ŠTEFL a Marek ŠEBESTA. Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor. Nucleic Acids Research. Oxford University Press, 2023, roč. 51, č. 6, s. 2818-2837. ISSN 0305-1048. Dostupné z: https://dx.doi.org/10.1093/nar/gkad092.

@article{2355898,
   author = {Hašanová, Zdenka and Klápšťová, Veronika and Porrua, Odil and Štefl, Richard and Šebesta, Marek},
   article_number = {6},
   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},
   language = {eng},
   issn = {0305-1048},
   journal = {Nucleic Acids Research},
   title = {Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor},
   url = {https://doi.org/10.1093/nar/gkad092},
   volume = {51},
   year = {2023}
}

TY  - JOUR
ID  - 2355898
AU  - Hašanová, Zdenka - Klápšťová, Veronika - Porrua, Odil - Štefl, Richard - Šebesta, Marek
PY  - 2023
TI  - Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor
JF  - Nucleic Acids Research
VL  - 51
IS  - 6
SP  - 2818-2837
EP  - 2818-2837
PB  - Oxford University Press
SN  - 03051048
KW  - RNA-POLYMERASE-II
KW  - OCULOMOTOR APRAXIA TYPE-2
KW  - SACCHAROMYCES-CEREVISIAE SEN1
KW  - GENOME INSTABILITY
KW  - REPLICATION CONFLICTS
KW  - RNA/DNA HYBRIDS
KW  - PAUSE SITES
KW  - INFO-RNA
KW  - HELICASE
KW  - ATAXIA
UR  - https://doi.org/10.1093/nar/gkad092
N2  - 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.
ER  -

HAŠANOVÁ, Zdenka, Veronika KLÁPŠŤOVÁ, Odil PORRUA, Richard ŠTEFL a Marek ŠEBESTA. Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor. \textit{Nucleic Acids Research}. Oxford University Press, 2023, roč.~51, č.~6, s.~2818-2837. ISSN~0305-1048. Dostupné z: https://dx.doi.org/10.1093/nar/gkad092.

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