A Hyper-IgM Syndrome Mutation in Activation-Induced Cytidine Deaminase Disrupts G-Quadruplex Binding and Genome-wide Chromatin Localization
| Autor: | Young Jun Kim, Davide Angeletti, Priyanka Chowdhury, William T. Yewdell, Adrian B. McDermott, Jonathan W. Yewdell, Ryan M. Smolkin, Keith C. Fernandez, Bharat Vaidyanathan, Jayanta Chaudhuri, Joseph C. Sun, Montserrat Cols, Kalina T. Belcheva, Colleen M. Lau, Wei-Feng Yen |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Hyper IgM syndrome Immunology Fluorescent Antibody Technique Somatic hypermutation Mice Transgenic Hyper-IgM Immunodeficiency Syndrome Lymphocyte Activation medicine.disease_cause Article Immunophenotyping Mice 03 medical and health sciences 0302 clinical medicine HLA Antigens Cytidine Deaminase medicine Activation-induced (cytidine) deaminase Animals Humans Immunology and Allergy B-Lymphocytes Mutation biology Gene Expression Profiling Computational Biology Germinal center Cytidine deaminase Germinal Center medicine.disease Immunoglobulin Class Switching Chromatin Cell biology Enzyme Activation G-Quadruplexes Disease Models Animal 030104 developmental biology Infectious Diseases Immunoglobulin class switching 030220 oncology & carcinogenesis biology.protein Disease Susceptibility Lymphoma Large B-Cell Diffuse Genome-Wide Association Study |
| Zdroj: | Immunity |
| ISSN: | 1074-7613 |
| DOI: | 10.1016/j.immuni.2020.10.003 |
| Popis: | Summary Precise targeting of activation-induced cytidine deaminase (AID) to immunoglobulin (Ig) loci promotes antibody class switch recombination (CSR) and somatic hypermutation (SHM), whereas AID targeting of non-Ig loci can generate oncogenic DNA lesions. Here, we examined the contribution of G-quadruplex (G4) nucleic acid structures to AID targeting in vivo. Mice bearing a mutation in Aicda (AIDG133V) that disrupts AID-G4 binding modeled the pathology of hyper-IgM syndrome patients with an orthologous mutation, lacked CSR and SHM, and had broad defects in genome-wide AIDG133V chromatin localization. Genome-wide analyses also revealed that wild-type AID localized to MHCII genes, and AID expression correlated with decreased MHCII expression in germinal center B cells and diffuse large B cell lymphoma. Our findings indicate a crucial role for G4 binding in AID targeting and suggest that AID activity may extend beyond Ig loci to regulate the expression of genes relevant to the physiology and pathology of activated B cells. |
| Databáze: | OpenAIRE |
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