A XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development

Abstract

We developed a Xrcc4M61R separation of function mouse line to overcome the embryonic lethality of Xrcc4 deficient mice. XRCC4M61R protein does not interact with Xlf, thus obliterating XRCC4-Xlf filament formation while preserving the ability to stabilize DNA Ligase IV. X4M61R mice, which are DNA repair deficient, phenocopy the Nhej1-/- (known as Xlf -/-) setting with a minor impact on the development of the adaptive immune system. The core NHEJ DNA repair factor XRCC4 is therefore not mandatory for V(D)J recombination aside from its role in stabilizing DNA ligase IV. In contrast, Xrcc4M61R mice crossed on Paxx-/-, Nhej1-/-, or Atm-/- backgrounds are severely immunocompromised, owing to aborted V(D)J recombination as in Xlf-Paxx and Xlf-Atm double KO settings. Furthermore, massive apoptosis of post-mitotic neurons causes embryonic lethality of Xrcc4M61R -Nhej1-/- double mutants. These in vivo results reveal new functional interplays between XRCC4 and PAXX, ATM and Xlf in mouse development and provide new insights in the understanding of the clinical manifestations of human XRCC4 deficient condition, in particular its absence of immune deficiency.

Data availability

The xl file with raw data used in PCA analysis (Fig. 2G) has been depositied on DRYADhttps://doi.org/10.5061/dryad.547d7wm7x

The following data sets were generated

Article and author information

Author details

  1. Benoit Roch

    DGSI Laboratory, Institut Imagine, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Vincent Abramowski

    DGSI Laboratory, Institut Imagine, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Olivier Etienne

    Laboratoire de RadioPathologie, CEA, Fontenay-aux Roses, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Stefania Musilli

    DGSI Laboratory, Institut Imagine, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Pierre David

    Transgenesis lab, Institut Imagine, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Jean-Baptiste Charbonnier

    Institute for Integrative Biology of the Cell (I2BC), CEA, Gif-s-Yvette, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Isabelle Callebaut

    Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, CNRS, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  8. François D Boussin

    Laboratoire de RadioPathologie, CEA, Fontenay-aux Roses, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Jean-Pierre de Villartay

    DGSI Laboratory, Institut Imagine, INSERM, Paris, France
    For correspondence
    jean-pierre.de-villartay@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5987-0463

Funding

Institut National de la Santé et de la Recherche Médicale

  • Benoit Roch
  • Vincent Abramowski
  • Stefania Musilli
  • Jean-Pierre de Villartay

Agence Nationale de la Recherche (ANR-10-IAHU-01)

  • Benoit Roch
  • Vincent Abramowski
  • Stefania Musilli
  • Pierre David
  • Jean-Pierre de Villartay

Institut National Du Cancer (PLBIO 16-280)

  • Benoit Roch
  • Vincent Abramowski
  • Stefania Musilli
  • Jean-Baptiste Charbonnier
  • Isabelle Callebaut
  • Jean-Pierre de Villartay

Ligue Contre le Cancer (Equipe Labellisée)

  • Benoit Roch
  • Vincent Abramowski
  • Stefania Musilli
  • Jean-Pierre de Villartay

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were performed in compliance with the French Ministry of Agriculture's regulations for animal experiments (act 87847, 19 October 1987; modified in May 2001) after audit with "Comité d'Ethique en Expérimentation Animale (CEEA) Paris Descartes" (Apafis #25432-2019041516286014 v6)

Reviewing Editor

  1. Ranjan Sen, National Institute on Aging, United States

Publication history

  1. Received: April 12, 2021
  2. Accepted: September 13, 2021
  3. Accepted Manuscript published: September 14, 2021 (version 1)
  4. Version of Record published: October 14, 2021 (version 2)

Copyright

© 2021, Roch et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Benoit Roch
  2. Vincent Abramowski
  3. Olivier Etienne
  4. Stefania Musilli
  5. Pierre David
  6. Jean-Baptiste Charbonnier
  7. Isabelle Callebaut
  8. François D Boussin
  9. Jean-Pierre de Villartay
(2021)
A XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development
eLife 10:e69353.
https://doi.org/10.7554/eLife.69353

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