Journal
IMMUNITY
Volume 53, Issue 5, Pages 952-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2020.10.003
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Funding
- Leukemia & Lymphoma Society
- National Institutes of Health (NIH) [CA009149]
- T32 award from the NIH [CA009149]
- Division of Intramural Research (DIR)
- National Institute of Allergy and Infectious Diseases (NIAID)
- NIH [R01AI072194, R01AI124186, R56AI072194, U54CA137788, P30CA008748]
- Ludwig Center for Cancer Immunotherapy
- Burroughs Wellcome Fund
- American Cancer Society
- Starr Cancer Research Foundation
- Ludwig Center for Cancer Immunotherapy, MSKCC Functional Genomics
- Geoffrey Beene Cancer Center - National Cancer Institute (NCI) Cancer Center Support Grant [P30 CA08748]
- Cycle for Survival
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
- NCI CCSG [P30 CA08748]
- Memorial Sloan Kettering Cancer Center
- Molecular Cytology Core Facility at Memorial Sloan Kettering Cancer Center [P30 CA008748]
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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 (AID(G133V)) 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 AID(G133V) 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.
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