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...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/69353 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T01:45:05Z |
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| id | doaj.art-9f2b7f8042e7416dbee800b5e8f5606b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:45:05Z |
| publishDate | 2021-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-9f2b7f8042e7416dbee800b5e8f5606b2022-12-22T03:53:06ZengeLife Sciences Publications LtdeLife2050-084X2021-09-011010.7554/eLife.69353An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid developmentBenoit Roch0Vincent Abramowski1Olivier Etienne2Stefania Musilli3Pierre David4Jean-Baptiste Charbonnier5Isabelle Callebaut6François D Boussin7Jean-Pierre de Villartay8https://orcid.org/0000-0001-5987-0463Université de Paris, Imagine Institute, Laboratory “Genome Dynamics in the Immune System”, INSERM UMR 1163, F-75015, Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, F75015, Paris, FranceUniversité de Paris, Imagine Institute, Laboratory “Genome Dynamics in the Immune System”, INSERM UMR 1163, F-75015, Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, F75015, Paris, FranceUniversité de Paris and Université Paris-Saclay, Inserm, LRP/iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, F-92265, Fontenay-aux-Roses, FranceUniversité de Paris, Imagine Institute, Laboratory “Genome Dynamics in the Immune System”, INSERM UMR 1163, F-75015, Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, F75015, Paris, FranceUniversité de Paris, Imagine Institute, Transgenesis facility, INSERM UMR 1163, F-75015, Paris, FranceInstitute for Integrative Biology of the Cell (I2BC), Institute Joliot, CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, F-91198, Gif-sur-Yvette Cedex, FranceSorbonne Université, Muséum National d'Histoire Naturelle, CNRS UMR 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, F-75005, Paris, FranceUniversité de Paris and Université Paris-Saclay, Inserm, LRP/iRCM/IBFJ CEA, UMR Stabilité Génétique Cellules Souches et Radiations, F-92265, Fontenay-aux-Roses, FranceUniversité de Paris, Imagine Institute, Laboratory “Genome Dynamics in the Immune System”, INSERM UMR 1163, F-75015, Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, F75015, Paris, FranceWe 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.https://elifesciences.org/articles/69353adaptive immune systemnon homologous end joiningv(d)j recombinationbrain development |
| spellingShingle | 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 eLife adaptive immune system non homologous end joining v(d)j recombination brain development |
| title | 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_short | 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 |
| topic | adaptive immune system non homologous end joining v(d)j recombination brain development |
| url | https://elifesciences.org/articles/69353 |
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