Anlysis of the induction of apoptosis by DNA mismatch

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K18428
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Fukuoka Dental College
• Principal Investigator: TAKEISHI YUKIMASA 福岡歯科大学, 口腔歯学部, 助教 (00758055)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ミスマッチ修復 / アポトーシス / クロマチン動態 / DNA複製 / 癌

Outline of Final Research Achievements

We provide the evidence showing that SMARCAD1, which has an ATP-dependent nucleosome remodeling activity, is a novel factor associated with the induction of MMR-dependent apoptosis. SMARCAD1 knockout cells (ΔSMARCAD1), as compared with control, were resistant to MNU, and the appearances of a sub-G1 population as well as caspase-9 activation were suppressed. Moreover, the MNU-induced mutant frequencies were increased in ΔSMARCAD1. In immunoprecipitation analysis, the formation of MMR complex in ΔSMARCAD1 was decreased as compared with control, and this effect was strongly dependent on the ATPase activity of SMARCAD1. Thus, we proposed the role of SMARCAD1 in the induction of apoptosis through the chromatin remodeling activity.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究によりMMR依存のアポトーシス誘導にはSMARCAD1のクロマチンリモデリング活性が重要であることが示唆された。遺伝性非ポリポーシス大腸がん(HNPCC:Hereditary nonpolyposis colorectal cancer)の発症原因はMMR遺伝子の変異によるものでることがよく知られている。そのためこの癌に対する抗がん剤の新たな分子基盤を提供することができた。またMMR依存のアポトーシス誘導にクロマチン動態が関わることが示されたことにより新たな研究領域を広げる学術的意義があったと考える。