| 研究実績の概要 |
In order to produce high affinity antibody, Immunoglobulin (Ig) gene locus of mature B cells undergoes Somatic Hyper Mutation (SHM) and Class Switch Recombination (CSR) upon antigen challenge. Activation-Induced Cytidine Deaminase (AID) is responsible for both by inducing DNA break for SHM and CSR, and recombination exclusively for CSR. Moreover, AID is also responsible for aberrant genomic rearrangement leading to oncogenic chromosomal translocations. The study aims to know how AID exerts such a function and the factors that regulate CSR and associated genomic instability.
(1) Utilizing BiFC technique we it revealed that AID forms monomer as well as dimer, and interacts with hnRNP proteins and Serbp1 to induce DNA break and recombination. The AID defective in Hyper-IgM-syndromeII was found to be dimerization defective, and also unable to interact with recombination specific RNA binding proteins. This study gives a plausible explanation for the impaired CSR but not SHM due to the defect of AID at the c-terminus in HIGM II.
(2) Appling candidate gene knockdown and targeted proteomics approaches, we identified novel regulatory factors that impact AID induced CSR and IgH/cMyc translocation. While the chromatin-remodeler SMARCA4 promoted AID-induced DNA break, other chromatin factors such as Brd2, SAMHD1, Phf5a/Sf3b14b promoted CSR and IgH/cMyc translocation by facilitating the recombination. The mode of action of each factor seems to be unique, which requires further study to understand their crosstalk in the regulation of AID induced genomic instability.
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