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

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Benoit Roch1,2, Vincent Abramowski1,2, Olivier Etienne3

  • 1Université de Paris, Imagine Institute, Laboratory "Genome Dynamics in the Immune System", INSERM UMR 1163, F-75015, Paris, France.

Elife
|September 14, 2021
PubMed

Insights

The study developed a novel mouse model to investigate the role of the DNA repair protein XRCC4 (X-ray repair cross-complementing protein 4). This model reveals XRCC4 is not essential for adaptive immunity, challenging previous understandings of DNA repair mechanisms.

Area of Science:

  • Molecular Biology
  • Genetics
  • Immunology

Background:

  • The DNA repair factor XRCC4 (X-ray repair cross-complementing protein 4) is crucial for non-homologous end-joining (NHEJ).
  • Complete deficiency in XRCC4 leads to embryonic lethality, hindering studies on its specific roles in DNA repair and development.
  • Previous research suggested XRCC4 is essential for V(D)J recombination and adaptive immune system development.

Purpose of the Study:

  • To create a separation-of-function mouse model for XRCC4 to bypass embryonic lethality and study its distinct roles.
  • To investigate the necessity of XRCC4 in V(D)J recombination and adaptive immunity.
  • To elucidate the interplay between XRCC4 and other DNA repair factors like XLF, PAXX, and ATM.

Main Methods:

  • Development of a separation-of-function mouse line expressing a mutated XRCC4 protein (XRCC4M61R) that cannot interact with XLF.
  • Analysis of DNA repair deficiency, V(D)J recombination efficiency, adaptive immune system development, and embryonic lethality in XRCC4M61R mice and double mutants.
  • Phenotypic characterization of mice with mutations in XRCC4, XLF (Nhej1), PAXX, and ATM.

Main Results:

  • The XRCC4M61R mutation disrupts XRCC4-XLF filament formation but preserves DNA ligase IV stabilization.
  • XRCC4M61R mice exhibit DNA repair deficiency and V(D)J recombination with only minor impacts on adaptive immunity, indicating XRCC4 is not mandatory for this process.
  • Double mutants of XRCC4 with Paxx, Nhej1, or Atm show severe immunodeficiency due to aborted V(D)J recombination and embryonic lethality caused by neuronal apoptosis.

Conclusions:

  • XRCC4's core function in stabilizing DNA ligase IV is separable from its role in XRCC4-XLF filament formation, which is dispensable for V(D)J recombination.
  • XRCC4 plays a critical, context-dependent role in V(D)J recombination and development, interacting with PAXX, ATM, and XLF.
  • These findings offer new insights into human XRCC4 deficiency conditions, particularly the observed lack of immune deficiency.
Keywords:
adaptive immune systembrain developmentchromosomesdevelopmental biologygene expressionmousenon homologous end joiningv(d)j recombination

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