RAG2’s Acidic Hinge Restricts Repair-Pathway Choice and Promotes Genomic Stability
V(D)J recombination-associated DNA double-strand breaks (DSBs) are normally repaired by the high-fidelity classical nonhomologous end-joining (cNHEJ) machinery. Previous studies implicated the recombination-activating gene (RAG)/DNA postcleavage complex (PCC) in regulating pathway choice by preventi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-09-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713004038 |
| _version_ | 1818367451502477312 |
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| author | Marc A. Coussens Rebecca L. Wendland Ludovic Deriano Cory R. Lindsay Suzzette M. Arnal David B. Roth |
| author_facet | Marc A. Coussens Rebecca L. Wendland Ludovic Deriano Cory R. Lindsay Suzzette M. Arnal David B. Roth |
| author_sort | Marc A. Coussens |
| collection | DOAJ |
| description | V(D)J recombination-associated DNA double-strand breaks (DSBs) are normally repaired by the high-fidelity classical nonhomologous end-joining (cNHEJ) machinery. Previous studies implicated the recombination-activating gene (RAG)/DNA postcleavage complex (PCC) in regulating pathway choice by preventing access to inappropriate repair mechanisms such as homologous recombination (HR) and alternative NHEJ (aNHEJ). Here, we report that RAG2’s “acidic hinge,” previously of unknown function, is critical for several key steps. Mutations that reduce the hinge’s negative charge destabilize the PCC, disrupt pathway choice, permit repair of RAG-mediated DSBs by the translocation-prone aNHEJ machinery, and reduce genomic stability in developing lymphocytes. Structural predictions and experimental results support our hypothesis that reduced flexibility of the hinge underlies these outcomes. Furthermore, sequence variants present in the human population reduce the hinge’s negative charge, permit aNHEJ, and diminish genomic integrity. |
| first_indexed | 2024-12-13T22:52:16Z |
| format | Article |
| id | doaj.art-5ad05996f98747ce8f92e7e4dde0d2bd |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-13T22:52:16Z |
| publishDate | 2013-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-5ad05996f98747ce8f92e7e4dde0d2bd2022-12-21T23:28:35ZengElsevierCell Reports2211-12472013-09-014587087810.1016/j.celrep.2013.07.041RAG2’s Acidic Hinge Restricts Repair-Pathway Choice and Promotes Genomic StabilityMarc A. Coussens0Rebecca L. Wendland1Ludovic Deriano2Cory R. Lindsay3Suzzette M. Arnal4David B. Roth5Department of Pathology, New York University School of Medicine, New York, NY 10016, USADepartment of Pathology, New York University School of Medicine, New York, NY 10016, USADepartment of Pathology, New York University School of Medicine, New York, NY 10016, USADepartment of Pathology, New York University School of Medicine, New York, NY 10016, USADepartment of Pathology, New York University School of Medicine, New York, NY 10016, USADepartment of Pathology, New York University School of Medicine, New York, NY 10016, USAV(D)J recombination-associated DNA double-strand breaks (DSBs) are normally repaired by the high-fidelity classical nonhomologous end-joining (cNHEJ) machinery. Previous studies implicated the recombination-activating gene (RAG)/DNA postcleavage complex (PCC) in regulating pathway choice by preventing access to inappropriate repair mechanisms such as homologous recombination (HR) and alternative NHEJ (aNHEJ). Here, we report that RAG2’s “acidic hinge,” previously of unknown function, is critical for several key steps. Mutations that reduce the hinge’s negative charge destabilize the PCC, disrupt pathway choice, permit repair of RAG-mediated DSBs by the translocation-prone aNHEJ machinery, and reduce genomic stability in developing lymphocytes. Structural predictions and experimental results support our hypothesis that reduced flexibility of the hinge underlies these outcomes. Furthermore, sequence variants present in the human population reduce the hinge’s negative charge, permit aNHEJ, and diminish genomic integrity.http://www.sciencedirect.com/science/article/pii/S2211124713004038 |
| spellingShingle | Marc A. Coussens Rebecca L. Wendland Ludovic Deriano Cory R. Lindsay Suzzette M. Arnal David B. Roth RAG2’s Acidic Hinge Restricts Repair-Pathway Choice and Promotes Genomic Stability Cell Reports |
| title | RAG2’s Acidic Hinge Restricts Repair-Pathway Choice and Promotes Genomic Stability |
| title_full | RAG2’s Acidic Hinge Restricts Repair-Pathway Choice and Promotes Genomic Stability |
| title_fullStr | RAG2’s Acidic Hinge Restricts Repair-Pathway Choice and Promotes Genomic Stability |
| title_full_unstemmed | RAG2’s Acidic Hinge Restricts Repair-Pathway Choice and Promotes Genomic Stability |
| title_short | RAG2’s Acidic Hinge Restricts Repair-Pathway Choice and Promotes Genomic Stability |
| title_sort | rag2 s acidic hinge restricts repair pathway choice and promotes genomic stability |
| url | http://www.sciencedirect.com/science/article/pii/S2211124713004038 |
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