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

Elife. 2021 Sep 14:10:e69353. doi: 10.7554/eLife.69353.

Abstract

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.

Keywords: adaptive immune system; brain development; chromosomes; developmental biology; gene expression; mouse; non homologous end joining; v(d)j recombination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Brain / embryology
  • Brain / metabolism
  • DNA End-Joining Repair*
  • DNA Ligase ATP / genetics
  • DNA Ligase ATP / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Humans
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation, Missense*
  • Neurons / metabolism
  • Neurons / pathology
  • Phenotype
  • Severe Combined Immunodeficiency / genetics*
  • Severe Combined Immunodeficiency / immunology
  • Severe Combined Immunodeficiency / metabolism
  • V(D)J Recombination*

Substances

  • DNA-Binding Proteins
  • Lig4 protein, mouse
  • Paxx protein, mouse
  • XLF protein, mouse
  • XRCC4 protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • DNA Ligase ATP

Associated data

  • Dryad/10.5061/dryad.547d7wm7x

Grants and funding

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