An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34519267.
- Also identified by DOI 10.7554/eLife.69353 and PMC identifier 8516412.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
We developed an <i>Xrcc4<sup>M61R</sup></i> separation of function mouse line to overcome the embryonic lethality of Xrcc4-deficient mice. XRCC4<sup>M61R</sup> protein does not interact with Xlf, thus obliterating XRCC4-Xlf filament formation while preserving the ability to stabilize DNA ligase IV. X4<sup>M61R</sup> mice, which are DNA repair deficient, phenocopy the <i>Nhej1-/-</i> (known as <i>Xlf</i> -/-) 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, <i>Xrcc4<sup>M61R</sup></i> mice crossed on <i>Paxx-/-</i>, <i>Nhej1-/-</i>, or <i>Atm</i>-/- backgrounds are severely immunocompromised, owing to aborted V(D)J recombination as in <i>Xlf-Paxx</i> and <i>Xlf-Atm</i> double Knock Out (DKO) settings. Furthermore, massive apoptosis of post-mitotic neurons causes embryonic lethality of <i>Xrcc4<sup>M61R</sup> -Nhej1-/-</i> 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 <i>XRCC4</i>-deficient condition, in particular its absence of immune deficiency.
Medical subject headings
- DNA End-Joining Repair
- DNA-Binding Proteins
- Lymphocytes
- Mutation, Missense
- Severe Combined Immunodeficiency
- V(D)J Recombination