Rtt105 regulates RPA function by configurationally stapling the flexible domains

Sahiti Kuppa, Jaigeeth Deveryshetty, Rahul Chadda, Jenna R. Mattice, Nilisha Pokhrel, Vikas Kaushik, Angela Patterson, Nalini Dhingra, Sushil Pangeni, Marisa K. Sadauskas, Sajad Shiekh, Hamza Balci, Taekjip Ha, Xiaolan Zhao, Brian Bothner and Edwin Antony ()
Additional contact information
Sahiti Kuppa: Saint Louis University School of Medicine
Jaigeeth Deveryshetty: Saint Louis University School of Medicine
Rahul Chadda: Saint Louis University School of Medicine
Jenna R. Mattice: Montana State University
Nilisha Pokhrel: Marquette University
Vikas Kaushik: Saint Louis University School of Medicine
Angela Patterson: Montana State University
Nalini Dhingra: Memorial Sloan Kettering Cancer Center
Sushil Pangeni: Johns Hopkins University
Marisa K. Sadauskas: Saint Louis University School of Medicine
Sajad Shiekh: Kent State University
Hamza Balci: Kent State University
Taekjip Ha: Johns Hopkins University
Xiaolan Zhao: Memorial Sloan Kettering Cancer Center
Brian Bothner: Montana State University
Edwin Antony: Saint Louis University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Replication 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.

Date: 2022
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DOI: 10.1038/s41467-022-32860-6

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