HDAC5, a Key Component in Temporal Regulation of p53-Mediated Transactivation in Response to Genotoxic Stress
HDAC5, a Key Component in Temporal Regulation of p53-Mediated Transactivation in Response to Genotoxic Stress
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DOI：
10.1016/j.molcel.2013.09.003
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发表时间：
2013-11-07
期刊：
影响因子：
16
通讯作者：
Das, Sanjeev
中科院分区：
文献类型：
--
作者：
Sen, Nirmalya;Kumari, Rajni;Das, Sanjeev
尽管是最充分研究的转录因子之一，但p53介导的转录的时间调节还不是很清楚。最近的数据表明，p53介导的反式激活的靶特异性是通过p53的翻译后修饰实现的。K120乙酰化是p53募集到促凋亡靶点的关键修饰。我们的数据显示，组蛋白去乙酰化酶5（HDAC5）结合p53和废除K120乙酰化，导致优先招聘p53的前逮捕和抗氧化剂的目标在早期阶段的压力。然而，在长期的遗传毒性应激下，HDAC5经历核输出。同时，p53在K120残基处被乙酰化，并选择性地反式激活促凋亡靶基因，导致凋亡的发生。此外，在HDAC5表达下调的小鼠中，在遗传毒性应激后，在高度脆弱的组织中细胞凋亡的发生加速。这些发现表明，HDAC5是p53介导的细胞命运决定的关键决定因素，以应对遗传毒性应激。
Despite being one of the most well-studied transcription factors, the temporal regulation of p53-mediated transcription is not very well understood. Recent data suggest that target specificity of p53-mediated transactivation is achieved by posttranslational modifications of p53. K120 acetylation is a modification critical for recruitment of p53 to proapoptotic targets. Our data reveal that histone deacetylase 5 (HDAC5) binds to p53 and abrogates K120 acetylation, resulting in preferential recruitment of p53 to proarrest and antioxidant targets at early phases of stress. However, upon prolonged genotoxic stress, HDAC5 undergoes nuclear export. Concomitantly, p53 is acetylated at the K120 residue and selectively transactivates proapoptotic target genes, leading to onset of apoptosis. Furthermore, upon genotoxic stress in mice where HDAC5 expression is downregulated, the onset of apoptosis is accelerated in the highly vulnerable tissues. These findings suggest that HDAC5 is a key determinant of p53-mediated cell fate decisions in response to genotoxic stress.