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MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair

Author

Listed:
  • Inge Krijger

    (The Netherlands Cancer Institute)

  • Bastian Föhr

    (Max-Planck Institute for Biophysical Chemistry)

  • Santiago Hernández Pérez

    (The Netherlands Cancer Institute)

  • Estelle Vincendeau

    (INSERM U1223, Institut Pasteur
    Université de Paris, Sorbonne Paris Cité)

  • Judit Serrat

    (The Netherlands Cancer Institute)

  • Alexander Marc Thouin

    (The Netherlands Cancer Institute)

  • Vivek Susvirkar

    (Max-Planck Institute for Biophysical Chemistry)

  • Chloé Lescale

    (INSERM U1223, Institut Pasteur)

  • Inés Paniagua

    (The Netherlands Cancer Institute)

  • Liesbeth Hoekman

    (The Netherlands Cancer Institute)

  • Simranjeet Kaur

    (Max-Planck Institute for Biophysical Chemistry)

  • Maarten Altelaar

    (The Netherlands Cancer Institute
    Utrecht Institute for Pharmaceutical Sciences, University of Utrecht)

  • Ludovic Deriano

    (INSERM U1223, Institut Pasteur)

  • Alex C. Faesen

    (Max-Planck Institute for Biophysical Chemistry)

  • Jacqueline J. L. Jacobs

    (The Netherlands Cancer Institute)

Abstract

MAD2L2 (REV7) plays an important role in DNA double-strand break repair. As a member of the shieldin complex, consisting of MAD2L2, SHLD1, SHLD2 and SHLD3, it controls DNA repair pathway choice by counteracting DNA end-resection. Here we investigated the requirements for shieldin complex assembly and activity. Besides a dimerization-surface, HORMA-domain protein MAD2L2 has the extraordinary ability to wrap its C-terminus around SHLD3, likely creating a very stable complex. We show that appropriate function of MAD2L2 within shieldin requires its dimerization, mediated by SHLD2 and accelerating MAD2L2-SHLD3 interaction. Dimerization-defective MAD2L2 impairs shieldin assembly and fails to promote NHEJ. Moreover, MAD2L2 dimerization, along with the presence of SHLD3, allows shieldin to interact with the TRIP13 ATPase, known to drive topological switches in HORMA-domain proteins. We find that appropriate levels of TRIP13 are important for proper shieldin (dis)assembly and activity in DNA repair. Together our data provide important insights in the dependencies for shieldin activity.

Suggested Citation

  • Inge Krijger & Bastian Föhr & Santiago Hernández Pérez & Estelle Vincendeau & Judit Serrat & Alexander Marc Thouin & Vivek Susvirkar & Chloé Lescale & Inés Paniagua & Liesbeth Hoekman & Simranjeet Kau, 2021. "MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25724-y
    DOI: 10.1038/s41467-021-25724-y
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    Cited by:

    1. Shiu Yeung Lam & Ruben Lugt & Aurora Cerutti & Zeliha Yalçin & Alexander M. Thouin & Marco Simonetta & Jacqueline J. L. Jacobs, 2024. "OTUD5 promotes end-joining of deprotected telomeres by promoting ATM-dependent phosphorylation of KAP1S824," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Estelle Vincendeau & Wenming Wei & Xuefei Zhang & Cyril Planchais & Wei Yu & Hélène Lenden-Hasse & Thomas Cokelaer & Juliana Pipoli da Fonseca & Hugo Mouquet & David J. Adams & Frederick W. Alt & Step, 2022. "SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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