Set domain-dependent regulation of transcriptional silencing and growth control by SUV39H1, a mammalian ortholog of Drosophila Su(var)3-9
Set domain-dependent regulation of transcriptional silencing and growth control by SUV39H1, a mammalian ortholog of Drosophila Su(var)3-9
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DOI：
10.1128/mcb.20.13.4900-4909.2000
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发表时间：
2000-07-01
影响因子：
5.3
通讯作者：
Cleary, ML
中科院分区：
文献类型：
--
作者：
Firestein, R;Cui, XM;Cleary, ML
哺乳动物 SET 结构域蛋白定义了一类独特的染色质相关因子，它们是生长控制信号和致癌激活的靶标。 SUV39H1 是果蝇 Su(var)3-9 的哺乳动物直系同源物，包含 SET 和铬结构域，这是蛋白质的特征基序，通过影响染色质结构的区域组织，有助于基因表达的表观遗传控制。在本报告中，我们证明，当 SUV39H1 通过 GAIA DNA 结合域与 DNA 结合时，SUV39H1 在瞬时转录测定中会抑制转录。在这些条件下，SUV39H1 显示出长程阻遏物的特征，能够在数千碱基范围内发挥作用以沉默基础启动子。外源表达的 SUV39H1 定位于核体，其形态特征表明间期细胞中存在异染色质，这支持了染色质介导的基因沉默中可能的作用。此外，我们还发现 SUV39H1 在 G(1)/S 细胞周期转变时特异性磷酸化，当强制表达时会抑制细胞生长。生长抑制以及 SUV39H1 形成核体和沉默转录的能力会被致癌抗磷酸酶 Sbf1 拮抗，当该酶过度表达时，会与 SET 结构域相互作用并稳定 SUV39H1 的磷酸化形式。这些研究提出了调节哺乳动物 su(var) 蛋白染色质组织活性的磷酸化依赖性机制，并暗示 SET 结构域作为将上游信号通路整合到表观遗传调控和生长控制的看门基序。
Mammalian SET domain-containing proteins define a distinctive class of chromatin-associated factors that are targets for growth control signals and oncogenic activation. SUV39H1, a mammalian ortholog of Drosophila Su(var)3-9, contains both SET and chrome domains, signature motifs for proteins that contribute to epigenetic control of gene expression through effects on the regional organization of chromatin structure. In this report we demonstrate that SUV39H1 represses transcription in a transient transcriptional assay when tethered to DNA through the GAIA DNA binding domain. Under these conditions, SUV39H1 displays features of a long-range repressor capable of acting over several kilobases to silence basal promoters. A possible role in chromatin-mediated gene silencing is supported by the localization of exogenously expressed SUV39H1 to nuclear bodies with morphologic features suggestive of heterochromatin in interphase cells. In addition, we show that SUV39H1 is phosphorylated specifically at the G(1)/S cell cycle transition and when forcibly expressed suppresses cell growth. Growth suppression as well as the ability of SUV39H1 to form nuclear bodies and silence transcription are antagonized by the oncogenic antiphosphatase Sbf1 that when hyperexpressed interacts with the SET domain and stabilizes the phosphorylated form of SUV39H1. These studies suggest a phosphorylation-dependent mechanism for regulating the chromatin organizing activity of a mammalian su(var) protein and implicate the SET domain as a gatekeeper motif that integrates upstream signaling pathways to epigenetic regulation and growth control.