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The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining
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| Zeitschriftentitel: | The Journal of Immunology |
|---|---|
| Personen und Körperschaften: | , , , , , , |
| In: | The Journal of Immunology, 196, 2016, 1, S. 244-255 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
The American Association of Immunologists
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| Schlagwörter: |
| author_facet |
Park, Jihye Welner, Robert S. Chan, Mei-Yee Troppito, Logan Staber, Philipp B. Tenen, Daniel G. Yan, Catherine T. Park, Jihye Welner, Robert S. Chan, Mei-Yee Troppito, Logan Staber, Philipp B. Tenen, Daniel G. Yan, Catherine T. |
|---|---|
| author |
Park, Jihye Welner, Robert S. Chan, Mei-Yee Troppito, Logan Staber, Philipp B. Tenen, Daniel G. Yan, Catherine T. |
| spellingShingle |
Park, Jihye Welner, Robert S. Chan, Mei-Yee Troppito, Logan Staber, Philipp B. Tenen, Daniel G. Yan, Catherine T. The Journal of Immunology The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining Immunology Immunology and Allergy |
| author_sort |
park, jihye |
| spelling |
Park, Jihye Welner, Robert S. Chan, Mei-Yee Troppito, Logan Staber, Philipp B. Tenen, Daniel G. Yan, Catherine T. 0022-1767 1550-6606 The American Association of Immunologists Immunology Immunology and Allergy http://dx.doi.org/10.4049/jimmunol.1403099 <jats:title>Abstract</jats:title> <jats:p>Hypomorphic mutations in the nonhomologous end-joining (NHEJ) DNA repair protein DNA ligase IV (LIG4) lead to immunodeficiency with varying severity. In this study, using a murine knock-in model, we investigated the mechanisms underlying abnormalities in class switch recombination (CSR) associated with the human homozygous Lig4 R278H mutation. Previously, we found that despite the near absence of Lig4 end-ligation activity and severely reduced mature B cell numbers, Lig4R278H/R278H (Lig4R/R) mice exhibit only a partial CSR block, producing near normal IgG1 and IgE but substantially reduced IgG3, IgG2b, and IgA serum levels. In this study, to address the cause of these abnormalities, we assayed CSR in Lig4R/R B cells generated via preassembled IgH and IgK V region exons (HL). This revealed that Lig4R278H protein levels while intact exhibited a higher turnover rate during activation of switching to IgG3 and IgG2b, as well as delays in CSR kinetics associated with defective proliferation during activation of switching to IgG1 and IgE. Activated Lig4R/RHL B cells consistently accumulated high frequencies of activation-induced cytidine deaminase–dependent IgH locus chromosomal breaks and translocations and were more prone to apoptosis, effects that appeared to be p53-independent, as p53 deficiency did not markedly influence these events. Importantly, NHEJ instead of alternative end-joining (A-EJ) was revealed as the predominant mechanism catalyzing robust CSR. Defective CSR was linked to failed NHEJ and residual A-EJ access to unrepaired double-strand breaks. These data firmly demonstrate that Lig4R278H activity renders NHEJ to be more error-prone, and they predict increased error-prone NHEJ activity and A-EJ suppression as the cause of the defective B lymphopoiesis in Lig4 patients.</jats:p> The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining The Journal of Immunology |
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| title |
The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining |
| title_unstemmed |
The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining |
| title_full |
The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining |
| title_fullStr |
The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining |
| title_full_unstemmed |
The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining |
| title_short |
The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining |
| title_sort |
the dna ligase iv syndrome r278h mutation impairs b lymphopoiesis via error-prone nonhomologous end-joining |
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Immunology Immunology and Allergy |
| url |
http://dx.doi.org/10.4049/jimmunol.1403099 |
| publishDate |
2016 |
| physical |
244-255 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Hypomorphic mutations in the nonhomologous end-joining (NHEJ) DNA repair protein DNA ligase IV (LIG4) lead to immunodeficiency with varying severity. In this study, using a murine knock-in model, we investigated the mechanisms underlying abnormalities in class switch recombination (CSR) associated with the human homozygous Lig4 R278H mutation. Previously, we found that despite the near absence of Lig4 end-ligation activity and severely reduced mature B cell numbers, Lig4R278H/R278H (Lig4R/R) mice exhibit only a partial CSR block, producing near normal IgG1 and IgE but substantially reduced IgG3, IgG2b, and IgA serum levels. In this study, to address the cause of these abnormalities, we assayed CSR in Lig4R/R B cells generated via preassembled IgH and IgK V region exons (HL). This revealed that Lig4R278H protein levels while intact exhibited a higher turnover rate during activation of switching to IgG3 and IgG2b, as well as delays in CSR kinetics associated with defective proliferation during activation of switching to IgG1 and IgE. Activated Lig4R/RHL B cells consistently accumulated high frequencies of activation-induced cytidine deaminase–dependent IgH locus chromosomal breaks and translocations and were more prone to apoptosis, effects that appeared to be p53-independent, as p53 deficiency did not markedly influence these events. Importantly, NHEJ instead of alternative end-joining (A-EJ) was revealed as the predominant mechanism catalyzing robust CSR. Defective CSR was linked to failed NHEJ and residual A-EJ access to unrepaired double-strand breaks. These data firmly demonstrate that Lig4R278H activity renders NHEJ to be more error-prone, and they predict increased error-prone NHEJ activity and A-EJ suppression as the cause of the defective B lymphopoiesis in Lig4 patients.</jats:p> |
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| author | Park, Jihye, Welner, Robert S., Chan, Mei-Yee, Troppito, Logan, Staber, Philipp B., Tenen, Daniel G., Yan, Catherine T. |
| author_facet | Park, Jihye, Welner, Robert S., Chan, Mei-Yee, Troppito, Logan, Staber, Philipp B., Tenen, Daniel G., Yan, Catherine T., Park, Jihye, Welner, Robert S., Chan, Mei-Yee, Troppito, Logan, Staber, Philipp B., Tenen, Daniel G., Yan, Catherine T. |
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| description | <jats:title>Abstract</jats:title> <jats:p>Hypomorphic mutations in the nonhomologous end-joining (NHEJ) DNA repair protein DNA ligase IV (LIG4) lead to immunodeficiency with varying severity. In this study, using a murine knock-in model, we investigated the mechanisms underlying abnormalities in class switch recombination (CSR) associated with the human homozygous Lig4 R278H mutation. Previously, we found that despite the near absence of Lig4 end-ligation activity and severely reduced mature B cell numbers, Lig4R278H/R278H (Lig4R/R) mice exhibit only a partial CSR block, producing near normal IgG1 and IgE but substantially reduced IgG3, IgG2b, and IgA serum levels. In this study, to address the cause of these abnormalities, we assayed CSR in Lig4R/R B cells generated via preassembled IgH and IgK V region exons (HL). This revealed that Lig4R278H protein levels while intact exhibited a higher turnover rate during activation of switching to IgG3 and IgG2b, as well as delays in CSR kinetics associated with defective proliferation during activation of switching to IgG1 and IgE. Activated Lig4R/RHL B cells consistently accumulated high frequencies of activation-induced cytidine deaminase–dependent IgH locus chromosomal breaks and translocations and were more prone to apoptosis, effects that appeared to be p53-independent, as p53 deficiency did not markedly influence these events. Importantly, NHEJ instead of alternative end-joining (A-EJ) was revealed as the predominant mechanism catalyzing robust CSR. Defective CSR was linked to failed NHEJ and residual A-EJ access to unrepaired double-strand breaks. These data firmly demonstrate that Lig4R278H activity renders NHEJ to be more error-prone, and they predict increased error-prone NHEJ activity and A-EJ suppression as the cause of the defective B lymphopoiesis in Lig4 patients.</jats:p> |
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| spelling | Park, Jihye Welner, Robert S. Chan, Mei-Yee Troppito, Logan Staber, Philipp B. Tenen, Daniel G. Yan, Catherine T. 0022-1767 1550-6606 The American Association of Immunologists Immunology Immunology and Allergy http://dx.doi.org/10.4049/jimmunol.1403099 <jats:title>Abstract</jats:title> <jats:p>Hypomorphic mutations in the nonhomologous end-joining (NHEJ) DNA repair protein DNA ligase IV (LIG4) lead to immunodeficiency with varying severity. In this study, using a murine knock-in model, we investigated the mechanisms underlying abnormalities in class switch recombination (CSR) associated with the human homozygous Lig4 R278H mutation. Previously, we found that despite the near absence of Lig4 end-ligation activity and severely reduced mature B cell numbers, Lig4R278H/R278H (Lig4R/R) mice exhibit only a partial CSR block, producing near normal IgG1 and IgE but substantially reduced IgG3, IgG2b, and IgA serum levels. In this study, to address the cause of these abnormalities, we assayed CSR in Lig4R/R B cells generated via preassembled IgH and IgK V region exons (HL). This revealed that Lig4R278H protein levels while intact exhibited a higher turnover rate during activation of switching to IgG3 and IgG2b, as well as delays in CSR kinetics associated with defective proliferation during activation of switching to IgG1 and IgE. Activated Lig4R/RHL B cells consistently accumulated high frequencies of activation-induced cytidine deaminase–dependent IgH locus chromosomal breaks and translocations and were more prone to apoptosis, effects that appeared to be p53-independent, as p53 deficiency did not markedly influence these events. Importantly, NHEJ instead of alternative end-joining (A-EJ) was revealed as the predominant mechanism catalyzing robust CSR. Defective CSR was linked to failed NHEJ and residual A-EJ access to unrepaired double-strand breaks. These data firmly demonstrate that Lig4R278H activity renders NHEJ to be more error-prone, and they predict increased error-prone NHEJ activity and A-EJ suppression as the cause of the defective B lymphopoiesis in Lig4 patients.</jats:p> The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining The Journal of Immunology |
| spellingShingle | Park, Jihye, Welner, Robert S., Chan, Mei-Yee, Troppito, Logan, Staber, Philipp B., Tenen, Daniel G., Yan, Catherine T., The Journal of Immunology, The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining, Immunology, Immunology and Allergy |
| title | The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining |
| title_full | The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining |
| title_fullStr | The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining |
| title_full_unstemmed | The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining |
| title_short | The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining |
| title_sort | the dna ligase iv syndrome r278h mutation impairs b lymphopoiesis via error-prone nonhomologous end-joining |
| title_unstemmed | The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining |
| topic | Immunology, Immunology and Allergy |
| url | http://dx.doi.org/10.4049/jimmunol.1403099 |