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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Genomic Instability*
  • HEK293 Cells
  • Humans
  • Mutation
  • R-Loop Structures*
  • RNA Polymerase II / metabolism
  • RNA Splicing
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • Stress, Physiological*
  • Structure-Activity Relationship
  • Transcription, Genetic*
  • Transcriptional Elongation Factors / chemistry
  • Transcriptional Elongation Factors / genetics
  • Transcriptional Elongation Factors / metabolism*


  • RNA, Messenger
  • Transcriptional Elongation Factors
  • transcription factor S-II
  • RNA Polymerase II