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.

Basic information

Original name

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

Authors

HAŠANOVÁ, Zdenka (703 Slovakia, belonging to the institution), Veronika KLÁPŠŤOVÁ (203 Czech Republic, belonging to the institution), Odil PORRUA, Richard ŠTEFL (203 Czech Republic, guarantor, belonging to the institution) and Marek ŠEBESTA (703 Slovakia, belonging to the institution)

Edition

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

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 14.900 in 2022

RIV identification code

RIV/00216224:14740/23:00132763

Organization unit

Central European Institute of Technology

DOI

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

UT WoS

000942750600001

Keywords in English

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

Abstract

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.

Links

EF18_046/0015974, research and development project

Name: Modernizace České infrastruktury pro integrativní strukturní biologii

GM21-10464M, research and development project

Name: Strukturní charakterizace interakcí mezi transkripcí a opravou DNA

Investor: Czech Science Foundation

649030, interní kód MU

Name: DECOR - Dynamic assembly and exchange of RNA polymerase II CTD factors (Acronym: DECOR)

Investor: European Union, DECOR, ERC (Excellent Science)

90127, large research infrastructures

Name: CIISB II

Citovat

HAŠANOVÁ, Zdenka, Veronika KLÁPŠŤOVÁ, Odil PORRUA, Richard ŠTEFL and Marek ŠEBESTA. Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor. Nucleic Acids Research. Oxford University Press, 2023, vol. 51, No 6, p. 2818-2837. ISSN 0305-1048. Available from: 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 and Marek ŠEBESTA. Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor. \textit{Nucleic Acids Research}. Oxford University Press, 2023, vol.~51, No~6, p.~2818-2837. ISSN~0305-1048. Available from: https://dx.doi.org/10.1093/nar/gkad092.

Detailed Information on Publication Record