| 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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| 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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