Impact of Nuclear De Novo NAD Synthesis via Histone Dynamics on DNA Repair during Cellular Senescence To Prevent Tumorigenesis
Impact of Nuclear De Novo NAD Synthesis via Histone Dynamics on DNA Repair during Cellular Senescence To Prevent Tumorigenesis
复制标题
通过组蛋白动力学进行核从头合成 NAD 对细胞衰老过程中 DNA 修复的影响以预防肿瘤发生
DOI：
10.1128/mcb.00379-22
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发表时间：
2022
影响因子：
5.3
通讯作者：
Ikura Tsuyoshi
中科院分区：
文献类型：
--
作者：
Ikura Masae;Furuya Kanji;Matsuda Tomonari;Ikura Tsuyoshi
NAD+合成是活细胞中的基本过程。局部代谢产物对染色质的影响影响染色质在DNA代谢中的表观遗传状态。我们先前已经表明，通过TIP 60的H2 AX的K5乙酰化是PARP-1的ADP核糖基化活性所需的，用于DNA损伤位点处的组蛋白H2 AX交换。然而，详细的分子机制仍不清楚。在这里，我们确定novoNAD合成酶1（NAD syn 1）作为一种新的结合伴侣H2 AX。NAD syn 1的酶活性对于PARP-1的ADP核糖基化活性对于DNA损伤位点处的H2 AX动力学是至关重要的。细胞核中NAD合成酶活性的抑制降低了总体细胞NAD+浓度，导致细胞衰老。因此，乙酰化依赖性H2 AX动力学和同源重组修复受到抑制，导致肿瘤发生增加。我们的研究结果揭示了细胞核中新NAD+的产生对于防止细胞衰老引起的DNA修复能力下降从而防止肿瘤发生的重要性。
NAD+synthesis is a fundamental process in living cells. The effects of local metabolite production on chromatin influence the epigenetic status of chromatin in DNA metabolism. We have previously shown that K5 acetylation of H2AX by TIP60 is required for the ADP ribosylation activity of PARP-1, for histone H2AX exchange at DNA damage sites. However, the detailed molecular mechanism has remained unclear. Here, we identifiedde novoNAD synthetase 1 (NAD syn1) as a novel binding partner to H2AX. The enzymatic activity of NAD syn1 is crucial for the ADP ribosylation activity of PARP-1 for the H2AX dynamics at sites of DNA damage. Inhibition of the NAD synthetase activity in the cell nucleus decreased the overall cellular NAD+concentration, leading to cellular senescence. Accordingly, the acetylation-dependent H2AX dynamics and homologous recombination repair were suppressed, leading to increased tumorigenesis. Our findings have revealed the importance ofde novoNAD+production in the cell nucleus for protection against the decreased DNA repair capacity caused by cellular senescence and thus against tumorigenesis.