An in vivo study of the impact of deficiency in the DNA repair proteins PAXX and XLF on development and maturation of the hemolymphoid system
© 2020 Musilli et al..
Repair of DNA double-strand breaks by the nonhomologous end joining pathway is central for proper development of the adaptive immune system. This repair pathway involves eight factors, including XRCC4-like factor (XLF)/Cernunnos and the paralog of XRCC4 and XLF, PAXX nonhomologous end joining factor (PAXX). Xlf-/- and Paxx-/- mice are viable and exhibit only a mild immunophenotype. However, mice lacking both PAXX and XLF are embryonic lethal because postmitotic neurons undergo massive apoptosis in embryos. To decipher the roles of PAXX and XLF in both variable, diversity, and joining recombination and immunoglobulin class switch recombination, here, using Cre/lox-specific deletion to prevent double-KO embryonic lethality, we developed two mouse models of a conditional Xlf KO in a Paxx-/- background. Cre expressed under control of the iVav or CD21 promoter enabled Xlf deletion in early hematopoietic progenitors and splenic mature B cells, respectively. We demonstrate the XLF and PAXX interplay during variable, diversity, and joining recombination in vivo but not during class switch recombination, for which PAXX appeared to be fully dispensable. Xlf/Paxx double KO in hematopoietic progenitors resulted in a shorter lifespan associated with onset of thymic lymphomas, revealing a genome caretaking function of XLF/PAXX.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:295 |
|---|---|
| Enthalten in: |
The Journal of biological chemistry - 295(2020), 8 vom: 21. Feb., Seite 2398-2406 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Musilli, Stefania [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 14.10.2020 Date Revised 17.03.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1074/jbc.AC119.010924 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM305145851 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM305145851 | ||
| 003 | DE-627 | ||
| 005 | 20231225120535.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1074/jbc.AC119.010924 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1017.xml |
| 035 | |a (DE-627)NLM305145851 | ||
| 035 | |a (NLM)31915249 | ||
| 035 | |a (PII)S0021-9258(17)48275-5 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Musilli, Stefania |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a An in vivo study of the impact of deficiency in the DNA repair proteins PAXX and XLF on development and maturation of the hemolymphoid system |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 14.10.2020 | ||
| 500 | |a Date Revised 17.03.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 Musilli et al. | ||
| 520 | |a Repair of DNA double-strand breaks by the nonhomologous end joining pathway is central for proper development of the adaptive immune system. This repair pathway involves eight factors, including XRCC4-like factor (XLF)/Cernunnos and the paralog of XRCC4 and XLF, PAXX nonhomologous end joining factor (PAXX). Xlf-/- and Paxx-/- mice are viable and exhibit only a mild immunophenotype. However, mice lacking both PAXX and XLF are embryonic lethal because postmitotic neurons undergo massive apoptosis in embryos. To decipher the roles of PAXX and XLF in both variable, diversity, and joining recombination and immunoglobulin class switch recombination, here, using Cre/lox-specific deletion to prevent double-KO embryonic lethality, we developed two mouse models of a conditional Xlf KO in a Paxx-/- background. Cre expressed under control of the iVav or CD21 promoter enabled Xlf deletion in early hematopoietic progenitors and splenic mature B cells, respectively. We demonstrate the XLF and PAXX interplay during variable, diversity, and joining recombination in vivo but not during class switch recombination, for which PAXX appeared to be fully dispensable. Xlf/Paxx double KO in hematopoietic progenitors resulted in a shorter lifespan associated with onset of thymic lymphomas, revealing a genome caretaking function of XLF/PAXX | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a DNA repair | |
| 650 | 4 | |a V(D)J recombination | |
| 650 | 4 | |a double-strand break | |
| 650 | 4 | |a gene knockout | |
| 650 | 4 | |a genetics | |
| 650 | 4 | |a immunogenetics | |
| 650 | 4 | |a immunoglobulin class switch recombination | |
| 650 | 4 | |a immunology | |
| 650 | 4 | |a lymphocyte | |
| 650 | 4 | |a lymphoma | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Paxx protein, mouse |2 NLM | |
| 650 | 7 | |a XLF protein, mouse |2 NLM | |
| 700 | 1 | |a Abramowski, Vincent |e verfasserin |4 aut | |
| 700 | 1 | |a Roch, Benoit |e verfasserin |4 aut | |
| 700 | 1 | |a de Villartay, Jean-Pierre |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of biological chemistry |d 1945 |g 295(2020), 8 vom: 21. Feb., Seite 2398-2406 |w (DE-627)NLM000004995 |x 1083-351X |7 nnns |
| 773 | 1 | 8 | |g volume:295 |g year:2020 |g number:8 |g day:21 |g month:02 |g pages:2398-2406 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1074/jbc.AC119.010924 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 295 |j 2020 |e 8 |b 21 |c 02 |h 2398-2406 | ||