A role for human senataxin in contending with pausing and backtracking during transcript elongation
Year: 2025
Type: article
Abstract: Senataxin (SETX) regulates RNA polymerase II (RNAPII) transcription and helps maintain genome stability, at least partly by suppressing R-loops. However, despite its importance in human disease, the precise function of SETX has remained unclear. Employing the degradation tag system for acute protein depletion, we demonstrate that SETX loss perturbs RNAPII elongation but does not markedly influence transcription termination at the end of genes. Through in vitro reconstitution of elongation, we show that SETX uses ATP-dependent RNA translocation to drive RNAPII forward across challenging DNA sequences, reminiscent of how bacterial ribosomes help mitigate RNAP pausing. In vivo, SETX depletion accordingly results in increased RNAPII pausing or backtracking, particularly during early elongation, with a corresponding, time-dependent local increase in R-loop formation. Together, these findings redefine our understanding of SETX's role in transcription and provide a mechanistic framework for interpreting R-loops and the causes of neurological disorders associated with SETX mutation.
Source: Molecular Cell
Authors: Zhong Han, Shiqing Fu, Jens Vilstrup Johansen, David Lopez Martinez, Jiangman Lou, Thierry Boissière, Dandan He, Daniel Blears, Anouk M. Olthof, A. Barbara Dirac-Svejstrup, Jesper Q. Svejstrup
Institution: University of Copenhagen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Funders: European Molecular Biology Organization, Wellcome Trust, Francis Crick Institute, Cancer Research UK, Novo Nordisk UK Research Foundation, National Research Foundation, Danmarks Grundforskningsfond, Novo Nordisk, Faculty of Health and Medical Sciences, University of Western Australia, Novo Nordisk Fonden, Medical Research Council, Det Sundhedsvidenskabelige Fakultet, Københavns Universitet
OpenAlex ID: W4416507546