IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-59133-2.html
   My bibliography  Save this article

Structural and functional insights into the interaction between Ku70/80 and Pol X family polymerases in NHEJ

Author

Listed:
  • Philippe Frit

    (Université Toulouse III—Paul Sabatier (UT3))

  • Himani Amin

    (University of Leicester)

  • Sayma Zahid

    (University of Leicester)

  • Nadia Barboule

    (Université Toulouse III—Paul Sabatier (UT3))

  • Chloe Hall

    (University of Leicester)

  • Gurdip Matharu

    (University of Leicester)

  • Steven W. Hardwick

    (Sanger Building, University of Cambridge)

  • Jeanne Chauvat

    (Université Toulouse III—Paul Sabatier (UT3))

  • Sébastien Britton

    (Université Toulouse III—Paul Sabatier (UT3))

  • Dima Y. Chirgadze

    (Sanger Building, University of Cambridge)

  • Virginie Ropars

    (Université Paris-Saclay)

  • Jean-Baptiste Charbonnier

    (Université Paris-Saclay)

  • Patrick Calsou

    (Université Toulouse III—Paul Sabatier (UT3))

  • Amanda K. Chaplin

    (University of Leicester)

Abstract

Non-homologous end joining (NHEJ) is the main repair pathway for double-strand DNA breaks (DSBs) in mammals. DNA polymerases lambda (Pol λ) and mu (Pol μ), members of the Pol X family, play a key role in this process. However, their interaction within the NHEJ complexes is unclear. Here, we present cryo-EM structures of Pol λ in complex with the DNA-PK long-range synaptic complex, and Pol μ bound to Ku70/80-DNA. These structures identify interaction sites between Ku70/80 and Pol X BRCT domains. Using mutants at the proteins interface in functional assays including cell transfection with an original gap-filling reporter, we define the role of the BRCT domain in the recruitment and activity of the two Pol X members in NHEJ and in their contribution to cell survival following DSBs. Finally, we propose a unified model for the interaction of all Pol X members with Ku70/80.

Suggested Citation

  • Philippe Frit & Himani Amin & Sayma Zahid & Nadia Barboule & Chloe Hall & Gurdip Matharu & Steven W. Hardwick & Jeanne Chauvat & Sébastien Britton & Dima Y. Chirgadze & Virginie Ropars & Jean-Baptiste, 2025. "Structural and functional insights into the interaction between Ku70/80 and Pol X family polymerases in NHEJ," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59133-2
    DOI: 10.1038/s41467-025-59133-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-59133-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-59133-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Siyu Chen & Linda Lee & Tasmin Naila & Susan Fishbain & Annie Wang & Alan E. Tomkinson & Susan P. Lees-Miller & Yuan He, 2021. "Structural basis of long-range to short-range synaptic transition in NHEJ," Nature, Nature, vol. 593(7858), pages 294-298, May.
    2. Andrea M. Kaminski & John M. Pryor & Dale A. Ramsden & Thomas A. Kunkel & Lars C. Pedersen & Katarzyna Bebenek, 2020. "Structural snapshots of human DNA polymerase μ engaged on a DNA double-strand break," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    3. Andrew Craxton & Deeksha Munnur & Rebekah Jukes-Jones & George Skalka & Claudia Langlais & Kelvin Cain & Michal Malewicz, 2018. "PAXX and its paralogs synergistically direct DNA polymerase λ activity in DNA repair," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Benjamin M. Stinson & Sean M. Carney & Johannes C. Walter & Joseph J. Loparo, 2024. "Structural role for DNA Ligase IV in promoting the fidelity of non-homologous end joining," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Angel Rivera-Calzada & Raquel Arribas-Bosacoma & Alba Ruiz-Ramos & Paloma Escudero-Bravo & Jasminka Boskovic & Rafael Fernandez-Leiro & Antony W. Oliver & Laurence H. Pearl & Oscar Llorca, 2022. "Structural basis for the inactivation of cytosolic DNA sensing by the vaccinia virus," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Jin H. Yang & Hugo B. Brandão & Anders S. Hansen, 2023. "DNA double-strand break end synapsis by DNA loop extrusion," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Metztli Cisneros-Aguirre & Felicia Wednesday Lopezcolorado & Linda Jillianne Tsai & Ragini Bhargava & Jeremy M. Stark, 2022. "The importance of DNAPKcs for blunt DNA end joining is magnified when XLF is weakened," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Xabier Vergara & Anna G. Manjón & Marcel Haas & Ben Morris & Ruben Schep & Christ Leemans & Anoek Friskes & Roderick L. Beijersbergen & Mathijs A. Sanders & René H. Medema & Bas Steensel, 2024. "Widespread chromatin context-dependencies of DNA double-strand break repair proteins," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. Andrea M. Kaminski & Kishore K. Chiruvella & Dale A. Ramsden & Katarzyna Bebenek & Thomas A. Kunkel & Lars C. Pedersen, 2022. "Analysis of diverse double-strand break synapsis with Polλ reveals basis for unique substrate specificity in nonhomologous end-joining," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    7. Aldo S. Bader & Martin Bushell, 2023. "iMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. Mariia Mikhova & Noah J. Goff & Tomáš Janovič & Joshua R. Heyza & Katheryn Meek & Jens C. Schmidt, 2024. "Single-molecule imaging reveals the kinetics of non-homologous end-joining in living cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    9. Qing Hu & Jose Espejo Valle-Inclán & Rashmi Dahiya & Alison Guyer & Alice Mazzagatti & Elizabeth G. Maurais & Justin L. Engel & Huiming Lu & Anthony J. Davis & Isidro Cortés-Ciriano & Peter Ly, 2024. "Non-homologous end joining shapes the genomic rearrangement landscape of chromothripsis from mitotic errors," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59133-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.