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

We developed aXrcc4M61R 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 theNhej1-/- (known asXlf -/-) 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 onPaxx-/-,Nhej1-/-, orAtm-/- backgrounds are severely immunocompromised, owing to aborted V(D)J recombination as inXlf-Paxx andXlf-Atm double KO settings. Furthermore, massive apoptosis of post-mitotic neurons causes embryonic lethality ofXrcc4M61R-Nhej1-/- double mutants. Thesein 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 humanXRCC4 deficient condition, in particular its absence of immune deficiency.
Source: eLife - Category: Biomedical Science Tags: Chromosomes and Gene Expression Developmental Biology Source Type: research