Regulatory mechanism of immunoglobulin diversification and genome instability through RNA-editing by AID

2018 Fiscal Year Final Research Report

• Project/Area Number: 15H05784
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: Honjo Tasuku 京都大学, 高等研究院, 特別教授 (80090504)
• Research Collaborator: Nasim Begam A. ; Kobayashi Maki ; Iwata So
• Project Period (FY): 2015-05-29 – 2019-03-31
• Keywords: DNA切断 / 組換え / 獲得免疫 / 免疫記憶

Outline of Final Research Achievements

By intracellular total RNA sequencing for detection of RNA editing by AID, several C to U editing candidates were obtained. Motif analysis of hnRNP K, revealed GXXG and RGG motifs involved in antibody gene diversification which is useful for identifying C to U editing candidate. We showed that the 3 'UTR of topoisomerase 1 (Top 1) mRNA mediates the repression of Top 1 translation by AID. In addition to FACT complex and H3K4, SMARCA4 was newly discovered as Top1 binding protein. We revealed that SMARCA4 is required for recruitment of Top1 to the antibody gene, and FACT functions as an adapter between Top1 and H3K4me3. While searching for factors that specifically accumulate in the S region, we analyzed the dNTPase, SAMHD1, and found for the first time the role that the intracellular dNTP pool plays in the DNA repair process of CSR. We also found that the splicing factor Phf5a is also a factor necessary for the DNA repair process.

Free Research Field

免疫ゲノム医学

Academic Significance and Societal Importance of the Research Achievements

AIDは、ワクチンの有効性を保証する獲得免疫における抗体多様化とその記憶形成の中心酵素である。AIDはTop1を介して抗体遺伝子の体細胞突然異とクラススイッチを行う一方、ミスターゲットによるゲノム不安定性を誘発する。本研究の成果は、AIDによる感染防御のみならず、高親和性IgAの腸内細菌制御を通して代謝制御に関わる仕組み、Top1制御異常による遺伝子変異が様々な遺伝性神経疾患の原因になる仕組みの解明に寄与するものであり、今まで不明であった免疫異常による代謝制御や複製非依存性転写依存性ゲノム不安定化の背景を明らかにする。