SMARCA5 facilitates cohesin localization at R-loops to prevent transcription-replication collisions

The cohesin complex is well recognized for maintaining sister chromatid cohesion during mitosis and meiosis, as well as for its role in genome organization through chromatin loop formation. Recent studies indicate that cohesin can be co-opted in cancer by aiding DNA repair processes to promote cancer cell proliferation. However, the mechanisms, protein partners, and functions by which cohesin is involved in DNA repair remain unclear. Here, we uncover a novel function of cohesin core subunits (RAD21, STAG1/2) in promoting transcription-coupled homologous recombination (TC-HR) at sites of R-loops. We demonstrate that cohesin (SMC1/3, RAD21, STAG1) preferentially localizes to R-loops in vitro and localize to DNA damage-induced R-loops in cells. Through a screen of chromatin remodelers, we identify that chromatin remodeler SMARCA5 recruits RAD21 and STAG at R-loop sites. SMARCA5 forms a complex with RAD21 via its SLIDE domain and is recruited to R-loops, providing a dual mechanism to promote the R-loop localization of the cohesin core subunits. The ATPase activity of SMARCA5 facilitates the localization of RAD21 and RAD51 at sites of R-loops to promote TC-HR and timely resolution of R-loops. Depletion of either core subunits of cohesin or SMARCA5, both of which are overexpressed in a subset of cancers, leads to aberrant R-loop accumulation, stalled replication fork progression, and elevated transcription-replication collision (TRC) events induced cell death. These findings shed new light on a previously unknown function of SMARCA5 through regulating cohesin core subunits RAD21/STAG at R-loops and established their potential as therapeutic targets in treating cancer.