An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development
Benoit Roch,
Vincent Abramowski,
Olivier Etienne,
Stefania Musilli,
Pierre David,
Jean-Baptiste Charbonnier,
Isabelle Callebaut,
François D Boussin,
Jean-Pierre de Villartay
Affiliations
Benoit Roch
Université de Paris, Imagine Institute, Laboratory “Genome Dynamics in the Immune System”, INSERM UMR 1163, F-75015, Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, F75015, Paris, France
Vincent Abramowski
Université de Paris, Imagine Institute, Laboratory “Genome Dynamics in the Immune System”, INSERM UMR 1163, F-75015, Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, F75015, Paris, France
Olivier Etienne
Université de Paris and Université Paris-Saclay, Inserm, LRP/iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, F-92265, Fontenay-aux-Roses, France
Stefania Musilli
Université de Paris, Imagine Institute, Laboratory “Genome Dynamics in the Immune System”, INSERM UMR 1163, F-75015, Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, F75015, Paris, France
Pierre David
Université de Paris, Imagine Institute, Transgenesis facility, INSERM UMR 1163, F-75015, Paris, France
Jean-Baptiste Charbonnier
Institute for Integrative Biology of the Cell (I2BC), Institute Joliot, CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, F-91198, Gif-sur-Yvette Cedex, France
Isabelle Callebaut
Sorbonne Université, Muséum National d'Histoire Naturelle, CNRS UMR 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, F-75005, Paris, France
François D Boussin
Université de Paris and Université Paris-Saclay, Inserm, LRP/iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, F-92265, Fontenay-aux-Roses, France
Université de Paris, Imagine Institute, Laboratory “Genome Dynamics in the Immune System”, INSERM UMR 1163, F-75015, Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, F75015, Paris, France
We developed an 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 non-homologous end-joining (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 Knock Out (DKO) 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 into the understanding of the clinical manifestations of human XRCC4-deficient condition, in particular its absence of immune deficiency.
