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Mol Cell. 2019 Oct 3;76(1):57-69.e9. doi: 10.1016/j.molcel.2019.07.037. Epub 2019 Sep 10.

Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability.

Author information

1
Mechanisms of Transcription Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
2
Bioinformatics and Biostatistics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
3
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide-Universidad de Sevilla, Seville, Spain.
4
Mechanisms of Transcription Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: jesper.svejstrup@crick.ac.uk.

Abstract

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.

KEYWORDS:

53BP1; DNA-RNA hybrids; R-loops; RNA polymerase II; TFIIS; backtracking; transcript cleavage; transcript elongation; transcription-associated genome instability

PMID:
31519522
DOI:
10.1016/j.molcel.2019.07.037
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