Nucleosome assembly proteins NAP1L1 and NAP1L4 modulate p53 acetylation to regulate cell fate.
Nucleosome assembly proteins NAP1L1 and NAP1L4 modulate p53 acetylation to regulate cell fate.
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核小体组装蛋白 NAP1L1 和 NAP1L4 调节 p53 乙酰化以调节细胞命运。
DOI：
10.1016/j.bbamcr.2019.118560
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Goto K
中科院分区：
文献类型：
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作者：
Tanaka T;Hozumi Y;Martelli AM;Iino M;Goto K
p53肿瘤抑制因子调节参与各种应激反应的基因的表达。在遗传毒性应激时，p53诱导调节细胞周期停滞的靶基因以存活或凋亡。然而，p53如何选择性地调节这些相反结果的详细机制仍不清楚。在这项研究中，我们研究了核小体组装蛋白1样1（NAP 1 L1）和NAP 1 L4，这两个被确定为DGK β-相互作用蛋白质的p53调控机制。在这里，我们证明，在正常条件下，NAP 1 L1敲低降低了p53的Lys 320乙酰化，减弱了p21的表达，而NAP 1 L4敲低增加了Lys 320乙酰化，增强了p21的表达。这些条件分别导致细胞生长的促进和抑制。在遗传毒性应激条件下，NAP 1 L1敲低增加了Lys 382乙酰化，增强了促凋亡Bax水平，从而促进细胞死亡。相比之下，NAP 1 L4敲低降低Lys 382乙酰化，减弱Bax水平，从而抑制细胞凋亡。这些结果表明，NAP 1 L1和NAP 1 L4调节细胞的命运，通过控制p53响应的前逮捕和促凋亡基因的表达，通过选择性调节p53乙酰化在特定的网站在正常的稳态和应激诱导的反应。
The p53 tumor suppressor regulates expression of genes involved in various stress responses. Upon genotoxic stress, p53 induces target genes regulating cell cycle arrest for survival or apoptosis. Nevertheless, detailed mechanisms of how p53 selectively regulates these opposing outcomes remain unclear. For this study, we investigated p53 regulatory mechanisms exerted by nucleosome assembly protein 1-like 1 (NAP1L1) and NAP1L4, both of which are identified as DGKζ-interacting proteins. Here we demonstrate that, under normal conditions, NAP1L1 knockdown decreases Lys320 acetylation of p53 with attenuated proarrest p21 expression, whereas NAP1L4 knockdown increases Lys320 acetylation with enhanced p21 expression. These conditions lead respectively to facilitation and suppression of cell growth. Under genotoxic stress conditions, NAP1L1 knockdown increases Lys382 acetylation with enhanced proapoptotic Bax levels, thereby facilitating cell death. By contrast, NAP1L4 knockdown decreases Lys382 acetylation with attenuated Bax levels, thereby suppressing apoptosis. These results suggest that NAP1L1 and NAP1L4 regulate cell fate by controlling the expression of p53-responsive proarrest and proapoptotic genes through selective modulation of p53 acetylation at specific sites during normal homeostasis and in stress-induced responses.