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2015 Fiscal Year Final Research Report

Mechanism for genome instability by activation induced cytidine deaminase induced-reduction of topoisomerase1

Research Project

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Project/Area Number 22000015
Research Category

Grant-in-Aid for Specially Promoted Research

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKyoto University

Principal Investigator

HONJO Tasuku  京都大学, 医学研究科, 客員教授 (80090504)

Co-Investigator(Renkei-kenkyūsha) NAGAOKA Hitoshi  京都大学, 医学研究科, 准教授 (20270647)
BEGUM Nasim Ara  京都大学, 医学研究科, 特定准教授 (80362507)
KOBAYASHI Maki  京都大学, 医学研究科, 特定准教授 (20400690)
Project Period (FY) 2010 – 2015
Keywords体細胞突然変異 / クラススイッチ組換え / RNA編集 / DNA修復
Outline of Final Research Achievements

Activation-induced cytidine deaminase (AID)-dependent immunological memory is engraved in immunoglobulin (IgH) gene and initiated by DNA breaks. Precise molecular mechanism of Topoisomerase1 (Top1)'s involvement in AID-induced DNA breaks was analyzed. This result corrected the previous DNA deamination theory. In type 5 hyper IgM syndrome caused by UNG deficiency, class switch recombination (CSR) is abolished, however, somatic hyper-mutation (SHM) is maintained. Molecular mechanism of UNG in CSR and SHM is analyzed and the results is sufficient for explaining this difference between these two syndrome. AIS has two independent functions of DNA breaks and DNA repair which are dependent on N-terminus and C-terminus domain of AID, respectively. The function-specific cofactors, hnRNP K for DNA breaks and hnRNP L for DNA repair are identified and analyzed. DNA breaks and repair steps are conducted in the chromatin structure. We showed that AID-induced IgH gene recombination requires the specific chromatin structure. Actually molecular function of chromatin remodeller SMARCA4, transcription elongation factor Spt4/5 complex and Brd4 which binds to acetylated lysine in IgH diversification were analyzed.

Free Research Field

生態系/医歯薬学

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Published: 2017-05-10   Modified: 2018-12-04  

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