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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals
2020
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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 |
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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 |
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