An unexpected role for Dicer as a reader of the unacetylated DNA binding domain of p53 in transcriptional regulation.
An unexpected role for Dicer as a reader of the unacetylated DNA binding domain of p53 in transcriptional regulation.
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Dicer作为p53的非乙酰化DNA结合域的阅读器在转录调控中的意外作用。
DOI：
10.1126/sciadv.abi6684
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发表时间：
2021-10-29
期刊：
影响因子：
13.6
通讯作者：
Gu W
中科院分区：
文献类型：
--
作者：
Yang X;Wang X;Li Z;Duan S;Li H;Jin J;Zhang Z;Gu W
Dicer作为一种意想不到的辅因子，以乙酰化依赖的方式调节p53靶点的启动子特异性调节。在这里，我们确定了切丁酶作为一个主要的细胞因子，识别的DNA结合结构域（DBD）的p53的乙酰化状态依赖的方式。在结合未乙酰化的DBD后，Dicer被募集到p53靶基因的启动子，在那里它抑制p53介导的转录激活。相反，内源性Dicer的敲低或敲除导致p53介导的转录激活的上调，而不增加其蛋白水平。此外，Dicer介导的抑制是独立于其内在的核糖核酸内切酶活性;相反，Dicer通过募集SUV 39 H1组蛋白甲基转移酶直接抑制转录。然而，在DNA损伤时，Dicer介导的阻遏被p53的DBD处的应激诱导的乙酰化废除。值得注意的是，乙酰化缺陷型p53- 3 KR在转录中的无能在Dicer表达丧失后部分但显著地恢复。我们的研究表明，Dicer作为一个意想不到的乙酰化的“读者”的p53，因此有重要的意义乙酰化介导的调节机制的p53转录程序。
Dicer acts as an unexpected cofactor in modulating promoter-specific regulation of p53 targets in an acetylation-dependent manner. Here, we identified Dicer as a major cellular factor that recognizes the DNA binding domain (DBD) of p53 in a manner dependent on its acetylation status. Upon binding the unacetylated DBD, Dicer is recruited to the promoters of p53 target genes, where it represses p53-mediated transcriptional activation. Conversely, knockdown or knockout of endogenous Dicer leads to up-regulation of p53-mediated transcriptional activation without increasing its protein levels. Moreover, Dicer-mediated repression is independent of its intrinsic endoribonuclease activity; instead, Dicer directly represses transcription by recruiting the SUV39H1 histone methyltransferase. However, upon DNA damage, Dicer-mediated repression is abrogated by stress-induced acetylation at the DBD of p53. Notably, the inability of acetylation-defective p53-3KR in transcription is partially but significantly restored upon loss of Dicer expression. Our study reveals that Dicer acts as an unexpected acetylation “reader” for p53 and thus has important implications regarding the mechanism of acetylation-mediated regulation of p53 transcriptional program.
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影响因子：
13.8
作者：
Guan, Kun-Liang;Xiong, Yue
通讯作者：
Xiong, Yue
影响因子：
28.2
作者：
Esteller M;Pandolfi PP
通讯作者：
Pandolfi PP
DOI：
10.1146/annurev.pathol.4.110807.092250
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Haigis MC;Sinclair DA
通讯作者：
Sinclair DA
DOI：
10.1073/pnas.51.5.786
发表时间：
1964-01-01
影响因子：
11.1
作者：
ALLFREY, VG;FAULKNER, R;MIRSKY, AE
通讯作者：
MIRSKY, AE
影响因子：
4.5
作者：
Gurtan, Allan M.;Lu, Victoria;Sharp, Phillip A.
通讯作者：
Sharp, Phillip A.