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Rtt105 regulates RPA function by configurationally stapling the flexible domains

Author

Listed:
  • 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
    Laronde Bio)

  • 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
    Johns Hopkins University
    Howard Hughes Medical Institute)

  • Xiaolan Zhao

    (Memorial Sloan Kettering Cancer Center)

  • Brian Bothner

    (Montana State University)

  • Edwin Antony

    (Saint Louis University School of Medicine
    Marquette University)

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.

Suggested Citation

  • Sahiti Kuppa & Jaigeeth Deveryshetty & Rahul Chadda & Jenna R. Mattice & Nilisha Pokhrel & Vikas Kaushik & Angela Patterson & Nalini Dhingra & Sushil Pangeni & Marisa K. Sadauskas & Sajad Shiekh & Ham, 2022. "Rtt105 regulates RPA function by configurationally stapling the flexible domains," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32860-6
    DOI: 10.1038/s41467-022-32860-6
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    References listed on IDEAS

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    1. Jaigeeth Deveryshetty & Rahul Chadda & Jenna R. Mattice & Simrithaa Karunakaran & Michael J. Rau & Katherine Basore & Nilisha Pokhrel & Noah Englander & James A. J. Fitzpatrick & Brian Bothner & Edwin, 2023. "Yeast Rad52 is a homodecamer and possesses BRCA2-like bipartite Rad51 binding modes," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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