Journal
MOLECULAR CELL
Volume 76, Issue 1, Pages 57-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2019.07.037
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Funding
- Advanced Sequencing Facility of the Francis Crick Institute (FCI)
- Proteomics Facility of the Francis Crick Institute (FCI)
- High Throughput Screening Facility of the Francis Crick Institute (FCI)
- FCI - Cancer Research UK [FC001166]
- UK Medical Research Council [FC001166]
- Wellcome Trust [FC001166]
- European Research Council [693327, ERC2014 AdG669898 TARLOOP]
- Spanish Ministry of Economy and Competitiveness [BFU2013-42918-P, BFU2016-75058-P]
- European Union (Fondo Europeo de Desarrollo Regional)
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Although correlations between RNA polymerase II (RNAPII) transcription stress, R-loops, and genome instability have been established, the mechanisms underlying these connections remain poorly understood. Here, we used a mutant version of the transcription elongation factor TFIIS (TFIISmut), aiming to specifically induce increased levels of RNAPII pausing, arrest, and/or backtracking in human cells. Indeed, TFIISmut expression results in slower elongation rates, relative depletion of polymerases from the end of genes, and increased levels of stopped RNAPII; it affects mRNA splicing and termination as well. Remarkably, TFIISmut expression also dramatically increases R-loops, which may form at the anterior end of backtracked RNAPII and trigger genome instability, including DNA strand breaks. These results shed light on the relationship between transcription stress and R-loops and suggest that different classes of R-loops may exist, potentially with distinct consequences for genome stability.
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