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

Journal Article: Molecular CellYear Published: (2019) Volume Number: 76, Article Number: 57-69.e9

Authors

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

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 (TFIIS), aiming to specifically induce increased levels of RNAPII pausing, arrest, and/or backtracking in human cells. Indeed, TFIIS 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, TFIIS 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.