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Elongation factor TFIIS prevents transcription stress and R-loop accumulation to maintain genome stability

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posted on 15.01.2020 by Diana Zatreanu, Zhong Han, Richard Mitter, Emanuela Tumini, Hannah Williams, Lea Gregersen, A Barbara Dirac-Svejstrup, Stefania Roma, Aengus Stewart, Andres Aguilera, Jesper Q Svejstrup
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.

Funding

Crick (Grant ID: 10166, Grant title: Svejstrup FC001166) European Research Council (Grant ID: 693327 - TRANSDAM, Grant title: ERC 693327 - TRANSDAM)

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