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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1)
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Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1)

机译：甲基转移酶Set7 / 9通过与Sirtuin 1（SIRT1）相互作用调节p53活性

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摘要

Numerous studies indicate that Sirtuin 1 (SIRT1), a mammalian nicotinamide adenine dinucleotide (NAD~+)-dependent histone deacetylase (HDAC), plays a crucial role in p53-mediated stress responses by deacetylating p53. Nevertheless, the acetylation levels of p53 are dramatically increased upon DNA damage, and it is not well understood how the SIRT1-p53 interaction is regulated during the stress responses. Here, we identified Set7/9 as a unique regulator of SIRT1. SIRT1 interacts with Set7/9 both in vitro and in vivo. In response to DNA damage in human cells, the interaction between Set7/9 and SIRT1 is significantly enhanced and coincident with an increase in p53 acetylation levels. Importantly, the interaction of SIRT1 and p53 is strongly suppressed in the presence of Set7/9. Consequently, SIRT1-mediated deacetylation of p53 is abrogated by Set7/9, and p53-mediated transactivation is increased during the DNA damage response. Of note, whereas SIRT1 can be methylated at multiple sites within its N terminus by Set7/9, a methylation-defective mutant of SIRT1 still retains its ability to inhibit p53 activity. Taken together, our results reveal that Set7/9 is a critical regulator of the SIRT1-p53 interaction and suggest that Set7/9 can modulate p53 function indirectly in addition to acting through a methylation-dependent mechanism.
机译：大量研究表明，Sirtuin 1（SIRT1）是哺乳动物烟酰胺腺嘌呤二核苷酸（NAD〜+）依赖的组蛋白脱乙酰基酶（HDAC），在p53介导的应激反应中通过使p53脱乙酰化发挥关键作用。然而，DNA损伤后，p53的乙酰化水平会显着增加，并且在应激反应期间如何调节SIRT1-p53相互作用尚不清楚。在这里，我们确定Set7 / 9是SIRT1的独特调节器。 SIRT1在体外和体内均与Set7 / 9相互作用。响应人类细胞中的DNA损伤，Set7 / 9与SIRT1之间的相互作用显着增强，并且与p53乙酰化水平的提高相吻合。重要的是，在Set7 / 9的存在下，SIRT1和p53的相互作用被强烈抑制。因此，Set7 / 9消除了SIRT1介导的p53脱乙酰基作用，并且在DNA损伤反应期间p53介导的反式激活增加了。值得注意的是，SIRT1可以在N末端的多个位点被Set7 / 9甲基化，而SIRT1的甲基化缺陷型突变体仍然保留了其抑制p53活性的能力。两者合计，我们的结果表明Set7 / 9是SIRT1-p53相互作用的关键调节器，并暗示Set7 / 9除了通过甲基化依赖性机制起作用外，还可以间接调节p53功能。

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    Xiangyu Liu; Donglai Wang; Ying Zhao; Bo Tu; Zhixing Zheng; Lina Wang; Haiying Wang; Wei Gu; Robert G. Roeder; Wei-Guo Zhu;

  • 作者单位

    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;

    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;

    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;

    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;

    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;

    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;

    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;

    lnstitute for Cancer Genetics, College of Physicians and Surgeons of Columbia University, New York, NY 10032;

    Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065;

    Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    p21~waf1/cip1; posttranslational modifications; tumor suppression;

    机译：p21〜waf1 / cip1;翻译后修饰;肿瘤抑制;

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