Transcription is essential for cellular function, but it can also lead to genetic instability, particularly through the formation of secondary structures such as R-loops, which consist of an RNA-DNA hybrid and a displaced DNA strand. Unscheduled R-loop accumulation is a major source of DNA damage and has been associated with several human diseases, including cancer. While multiple factors involved in RNA biogenesis, export, and chromatin remodeling play a role in preventing R-loop accumulation, the function of essential proteins in R-loop metabolism remains unexplored. Here, we performed a genetic screening in Saccharomyces cerevisiae using over 1200 temperature-sensitive mutants to identify novel proteins involved in the prevention of R-loop-associated genomic instability. Our results reveal that the SWI/SNF-like protein Mot1 plays a key role in preventing R-loop accumulation and R-loop-associated genome instability. Its role is particularly important during S phase, where Mot1 dysfunction leads to R-loop dependent replication impairment, presumably due to transcription-replication conflicts (TRCs). Epistatic relationships between mutations in MOT1 and the S-phase specific DNA-RNA helicase SEN1 further support the role of Mot1 in TRCs. The study highlights the importance of transcriptional regulators in maintaining genome stability by mitigating TRCs and regulating R-loop homeostasis.

• PMID: 41662397
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Journal Article

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Soler-Oliva ME, Domínguez-Sierra RA, Gaillard H, Aguilera A

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