15th EDRA Webinar - March 25th, 2025

15th EDRA Webinar

March 25th, 2025, from 4:00 to 5:30 pm (CET)

Prof. Fredrik Westerlund - Keynote speaker 

Chalmers University of Technology, Gothenburg, Sweden

TBD

TBD 

Sidrit Uruci - short talk

SMARCAD1 regulates R-loops at active replication forks linked to cancer mutation hotspots

DNA replication forks often encounter obstacles during their progression such as the stalled transcription machinery and R-loops. While ribonucleases and DNA-RNA helicases can resolve these structures, the role of chromatin remodelers remains understudied. In this study, we describe an additional and independent role for chromatin remodeler SMARCAD1 in processing R-loops in proximity of active replication forks. Through a series of in vitro biochemical assays, single molecule atomic force microscopy and in silico predictions through AlphaFold3 software, we demonstrate that SMARCAD1 directly binds to R-loops through its ATPase domain. Utilizing functional mutants of human SMARCAD1, which either lacks the association to the replication forks (NΔ-SMARCAD1) or is defective in its nucleosome remodeling activity (K528R-SMARCAD1) for in situ artificial tethering and in vivo genetic studies, we captured high levels of transcription-replication conflicts (TRCs) and R-loops accumulation in the vicinity of ongoing and unstressed replication forks. The regions accumulating R-loops in SMARCAD1-mutant cell lines are distinct from those previously identified as prone to replication fork breakage. Additionally, regions with R-loop accumulation in SMARCAD1 mutant cells exhibit increased mutagenesis specifically in germline tumors, suggesting they are mutation hotspots in cancer. Our study unveils SMARCAD1 as an autonomous chromatin remodeler capable of directly binding the R-loops, thus facilitating their processing, and TRCs ahead of replication forks, emerging as a key player in maintaining genome stability and preventing tumorigenesis.

Agnese Cristini - short talk

Cancer Research Center CRCT, Toulouse, France

TBD

TBD