Cargando…

Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI

Non-homologous end-joining (NHEJ) is a DNA repair pathway required to detect, process, and ligate DNA double-stranded breaks (DSBs) throughout the cell cycle. The NHEJ pathway is necessary for V(D)J recombination in developing B and T lymphocytes. During NHEJ, Ku70 and Ku80 form a heterodimer that r...

Descripción completa

Detalles Bibliográficos
Autores principales: Castañeda-Zegarra, Sergio, Zhang, Qindong, Alirezaylavasani, Amin, Fernandez-Berrocal, Marion, Yao, Rouan, Oksenych, Valentyn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762521/
https://www.ncbi.nlm.nih.gov/pubmed/33289702
http://dx.doi.org/10.18632/aging.202346
_version_ 1783627825672093696
author Castañeda-Zegarra, Sergio
Zhang, Qindong
Alirezaylavasani, Amin
Fernandez-Berrocal, Marion
Yao, Rouan
Oksenych, Valentyn
author_facet Castañeda-Zegarra, Sergio
Zhang, Qindong
Alirezaylavasani, Amin
Fernandez-Berrocal, Marion
Yao, Rouan
Oksenych, Valentyn
author_sort Castañeda-Zegarra, Sergio
collection PubMed
description Non-homologous end-joining (NHEJ) is a DNA repair pathway required to detect, process, and ligate DNA double-stranded breaks (DSBs) throughout the cell cycle. The NHEJ pathway is necessary for V(D)J recombination in developing B and T lymphocytes. During NHEJ, Ku70 and Ku80 form a heterodimer that recognizes DSBs and promotes recruitment and function of downstream factors PAXX, MRI, DNA-PKcs, Artemis, XLF, XRCC4, and LIG4. Mutations in several known NHEJ genes result in severe combined immunodeficiency (SCID). Inactivation of Mri, Paxx or Xlf in mice results in normal or mild phenotype, while combined inactivation of Xlf/Mri, Xlf/Paxx, or Xlf/Dna-pkcs leads to late embryonic lethality. Here, we describe three new mouse models. We demonstrate that deletion of Trp53 rescues embryonic lethality in mice with combined deficiencies of Xlf and Mri. Furthermore, Xlf(-/-)Mri(-/-)Trp53(+/-) and Xlf(-/-)Paxx(-/-)Trp53(+/-) mice possess reduced body weight, severely reduced mature lymphocyte counts, and accumulation of progenitor B cells. We also report that combined inactivation of Mri/Paxx results in live-born mice with modest phenotype, and combined inactivation of Mri/Dna-pkcs results in embryonic lethality. Therefore, we conclude that XLF is functionally redundant with MRI and PAXX during lymphocyte development in vivo. Moreover, Mri genetically interacts with Dna-pkcs and Paxx.
format Online
Article
Text
id pubmed-7762521
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Impact Journals
record_format MEDLINE/PubMed
spelling pubmed-77625212021-01-08 Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI Castañeda-Zegarra, Sergio Zhang, Qindong Alirezaylavasani, Amin Fernandez-Berrocal, Marion Yao, Rouan Oksenych, Valentyn Aging (Albany NY) Research Paper Non-homologous end-joining (NHEJ) is a DNA repair pathway required to detect, process, and ligate DNA double-stranded breaks (DSBs) throughout the cell cycle. The NHEJ pathway is necessary for V(D)J recombination in developing B and T lymphocytes. During NHEJ, Ku70 and Ku80 form a heterodimer that recognizes DSBs and promotes recruitment and function of downstream factors PAXX, MRI, DNA-PKcs, Artemis, XLF, XRCC4, and LIG4. Mutations in several known NHEJ genes result in severe combined immunodeficiency (SCID). Inactivation of Mri, Paxx or Xlf in mice results in normal or mild phenotype, while combined inactivation of Xlf/Mri, Xlf/Paxx, or Xlf/Dna-pkcs leads to late embryonic lethality. Here, we describe three new mouse models. We demonstrate that deletion of Trp53 rescues embryonic lethality in mice with combined deficiencies of Xlf and Mri. Furthermore, Xlf(-/-)Mri(-/-)Trp53(+/-) and Xlf(-/-)Paxx(-/-)Trp53(+/-) mice possess reduced body weight, severely reduced mature lymphocyte counts, and accumulation of progenitor B cells. We also report that combined inactivation of Mri/Paxx results in live-born mice with modest phenotype, and combined inactivation of Mri/Dna-pkcs results in embryonic lethality. Therefore, we conclude that XLF is functionally redundant with MRI and PAXX during lymphocyte development in vivo. Moreover, Mri genetically interacts with Dna-pkcs and Paxx. Impact Journals 2020-12-07 /pmc/articles/PMC7762521/ /pubmed/33289702 http://dx.doi.org/10.18632/aging.202346 Text en Copyright: © 2020 Castañeda-Zegarra et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Castañeda-Zegarra, Sergio
Zhang, Qindong
Alirezaylavasani, Amin
Fernandez-Berrocal, Marion
Yao, Rouan
Oksenych, Valentyn
Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI
title Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI
title_full Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI
title_fullStr Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI
title_full_unstemmed Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI
title_short Leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors XLF and MRI
title_sort leaky severe combined immunodeficiency in mice lacking non-homologous end joining factors xlf and mri
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762521/
https://www.ncbi.nlm.nih.gov/pubmed/33289702
http://dx.doi.org/10.18632/aging.202346
work_keys_str_mv AT castanedazegarrasergio leakyseverecombinedimmunodeficiencyinmicelackingnonhomologousendjoiningfactorsxlfandmri
AT zhangqindong leakyseverecombinedimmunodeficiencyinmicelackingnonhomologousendjoiningfactorsxlfandmri
AT alirezaylavasaniamin leakyseverecombinedimmunodeficiencyinmicelackingnonhomologousendjoiningfactorsxlfandmri
AT fernandezberrocalmarion leakyseverecombinedimmunodeficiencyinmicelackingnonhomologousendjoiningfactorsxlfandmri
AT yaorouan leakyseverecombinedimmunodeficiencyinmicelackingnonhomologousendjoiningfactorsxlfandmri
AT oksenychvalentyn leakyseverecombinedimmunodeficiencyinmicelackingnonhomologousendjoiningfactorsxlfandmri