The role of acetylation-dependent nuclear NAD metabolism in damaged chromatin dynamics
| Project/Area Number |
17H01875
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Risk sciences of radiation and chemicals
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| Research Institution | Kyoto University |
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Principal Investigator |
Ikura Tsuyoshi 京都大学, 生命科学研究科, 准教授 (70335686)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
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| Keywords | TIP60 / NAD代謝 / H2AX / アセチル化 / TIP60ヒストンアセチル化酵素 / ヒストンH2AX / クロマチン / 放射線感受性 |
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| Outline of Final Research Achievements |
We have previously shown that the acetylation of histone H2AX by TIP60 is required for the ADP ribosylation activity of PARP-1 for H2AX exchange at DNA damage sites. However, it remains unknown how the acetylation of H2AX by TIP60 activates the ADP ribosylation activity of PARP-1. In this time, we identified NAD synthetase 1 (NADS1), which is responsible for de novo NAD production, in the purified H2AX complex. Chromatin immunoprecipitation analysis revealed that the acetylation of H2AX by TIP60 is required for the accumulation of NADS1 at DNA damage sites. When NADS1 mutant, which lacks its enzymatic activity, was overexpressed in only cell nucleus, dynamic binding of PARP-1 to damaged chromatin was reduced. It suggests that the NADS1 contributes to local production of NAD for PARP-1 dynamics at DNA damage sites. The depletion of NADS1 in cells failed to homologous recombination repair. Our results indicate the importance of nuclear NADS1 in damaged chromatin dynamics.
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| Academic Significance and Societal Importance of the Research Achievements |
本課題により細胞核内のde novo NAD産生系がゲノムストレス損傷応答に関与することが明らかになった。これまでNAD産生系は、細胞質にのみ存在すると考えられていたが、今回の発見は、NAD 代謝系とTIP60によるH2AXのアセチル化によるH2AXの交換反応が細胞核内で密接に連携していることを示しており、クロマチン制御に対しての新たな視点を提供でき、学術的に意義深い。また本研究は、エネルギー代謝との関連から将来的には生活習慣病、老化シグナルについてクロマチン制御を介したゲノムストレス応答研究の視点からのアプローチが可能となり、社会的貢献度の高い研究としての発展が期待できる。
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Report
(4 results)
Research Products
(32 results)
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[Journal Article] Distinct roles of ATM and ATR in the regulation of ARP8 phosphorylation to prevent chromosome translocations2018
Author(s)
Sun, J., Shi, L., Kinomura, A., Fukuto, A., Horikoshi, Y., Oma, Y., Harata, M., Ikura, M., Ikura, T., Kanaar, R., Tashiro, S
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Journal Title
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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