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Item Rtt105 regulates RPA function by configurationally stapling the flexible domains(Springer Science and Business Media LLC, 2022-09) Kuppa, Sahiti; Deveryshetty, Jaigeeth; Chadda, Rahul; Mattice, Jenna R.; Pokhrel, Nilisha; Kaushik, Vikas; Patterson, Angela; Dhingra, Nalini; Pangeni, Sushil; Sadauskas, Marisa K.; Shiekh, Sajad; Balci, Hamza; Ha, Taekjip; Zhao, Xiaolan; Bothner, Brian; Antony, EdwinReplication Protein A (RPA) is a heterotrimeric complex that binds to single-stranded DNA (ssDNA) and recruits over three dozen RPA-interacting proteins to coordinate multiple aspects of DNA metabolism including DNA replication, repair, and recombination. Rtt105 is a molecular chaperone that regulates nuclear localization of RPA. Here, we show that Rtt105 binds to multiple DNA binding and protein-interaction domains of RPA and configurationally staples the complex. In the absence of ssDNA, Rtt105 inhibits RPA binding to Rad52, thus preventing spurious binding to RPA-interacting proteins. When ssDNA is available, Rtt105 promotes formation of high-density RPA nucleoprotein filaments and dissociates during this process. Free Rtt105 further stabilizes the RPA-ssDNA filaments by inhibiting the facilitated exchange activity of RPA. Collectively, our data suggest that Rtt105 sequesters free RPA in the nucleus to prevent untimely binding to RPA-interacting proteins, while stabilizing RPA-ssDNA filaments at DNA lesion sites.