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

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 re...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Benoit Roch, Vincent Abramowski, Olivier Etienne, Stefania Musilli, Pierre David, Jean-Baptiste Charbonnier, Isabelle Callebaut, François D Boussin, Jean-Pierre de Villartay
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	adaptive immune system non homologous end joining v(d)j recombination brain development Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/9f2b7f8042e7416dbee800b5e8f5606b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:9f2b7f8042e7416dbee800b5e8f5606b
record_format	dspace
spelling	oai:doaj.org-article:9f2b7f8042e7416dbee800b5e8f5606b2021-11-29T12:11:40ZAn XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development10.7554/eLife.693532050-084Xe69353https://doaj.org/article/9f2b7f8042e7416dbee800b5e8f5606b2021-09-01T00:00:00Zhttps://elifesciences.org/articles/69353https://doaj.org/toc/2050-084XWe 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.Benoit RochVincent AbramowskiOlivier EtienneStefania MusilliPierre DavidJean-Baptiste CharbonnierIsabelle CallebautFrançois D BoussinJean-Pierre de VillartayeLife Sciences Publications Ltdarticleadaptive immune systemnon homologous end joiningv(d)j recombinationbrain developmentMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	adaptive immune system non homologous end joining v(d)j recombination brain development Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	adaptive immune system non homologous end joining v(d)j recombination brain development Medicine R Science Q Biology (General) QH301-705.5 Benoit Roch Vincent Abramowski Olivier Etienne Stefania Musilli Pierre David Jean-Baptiste Charbonnier Isabelle Callebaut François D Boussin Jean-Pierre de Villartay An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development
description	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.
format	article
author	Benoit Roch Vincent Abramowski Olivier Etienne Stefania Musilli Pierre David Jean-Baptiste Charbonnier Isabelle Callebaut François D Boussin Jean-Pierre de Villartay
author_facet	Benoit Roch Vincent Abramowski Olivier Etienne Stefania Musilli Pierre David Jean-Baptiste Charbonnier Isabelle Callebaut François D Boussin Jean-Pierre de Villartay
author_sort	Benoit Roch
title	An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development
title_short	An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development
title_full	An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development
title_fullStr	An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development
title_full_unstemmed	An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development
title_sort	xrcc4 mutant mouse, a model for human x4 syndrome, reveals interplays with xlf, paxx, and atm in lymphoid development
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/9f2b7f8042e7416dbee800b5e8f5606b
work_keys_str_mv	AT benoitroch anxrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT vincentabramowski anxrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT olivieretienne anxrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT stefaniamusilli anxrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT pierredavid anxrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT jeanbaptistecharbonnier anxrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT isabellecallebaut anxrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT francoisdboussin anxrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT jeanpierredevillartay anxrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT benoitroch xrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT vincentabramowski xrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT olivieretienne xrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT stefaniamusilli xrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT pierredavid xrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT jeanbaptistecharbonnier xrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT isabellecallebaut xrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT francoisdboussin xrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment AT jeanpierredevillartay xrcc4mutantmouseamodelforhumanx4syndromerevealsinterplayswithxlfpaxxandatminlymphoiddevelopment
_version_	1718407417338789888

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

Ejemplares similares