ATM Substrate Chk2-interacting Zn2+ Finger (ASCIZ) Is a Bi-functional Transcriptional Activator and Feedback Sensor in the Regulation of Dynein Light Chain (DYNLL1) Expression
ATM Substrate Chk2-interacting Zn2+ Finger (ASCIZ) Is a Bi-functional Transcriptional Activator and Feedback Sensor in the Regulation of Dynein Light Chain (DYNLL1) Expression
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DOI：
10.1074/jbc.m111.306019
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发表时间：
2012-01-27
影响因子：
4.8
通讯作者：
Heierhorst, Joerg
中科院分区：
文献类型：
--
作者：
Jurado, Sabine;Conlan, Lindus A.;Heierhorst, Joerg
高度保守的DYNLL1 （LC8）蛋白最初被发现是动力蛋白运动复合物的一个轻链，但越来越多地作为蛋白质二聚化的序列特异性调节剂出现，具有数百个靶点和广泛的细胞功能。尽管DYNLL1具有重要作用，但人们对其自身的调控仍知之甚少。在这里，我们确定了ASCIZ (ATMIN/ZNF822)，一个重要的Zn2+指蛋白，在DNA碱基损伤反应中具有双重作用，作为一个发育转录因子，作为Dynll1基因表达的保守调节因子。在人、小鼠和鸡细胞中，缺乏ASCIZ时DYNLL1水平降低了10倍。ASCIZ直接与Dynll1启动子结合，并以依赖于Zn2+指的方式调节其活性。DYNLL1蛋白反过来与ASCIZ转录激活域中的10个结合位点相互作用，高水平的DYNLL1抑制ASCIZ的转录活性。此外，DNA损伤诱导的ASCIZ病灶形成也需要DYNLL1。ASCIZ激活Dynll1基因表达和感知游离Dynll1蛋白水平的双重能力使得一个简单的动态反馈回路能够根据细胞需要调整Dynll1水平。ASCIZ-DYNLL1反馈回路代表了一种基因表达自动调节的新机制，其中基因产物在其自身启动子结合时直接抑制转录激活子。
The highly conserved DYNLL1 (LC8) protein was originally discovered as a light chain of the dynein motor complex, but is increasingly emerging as a sequence-specific regulator of protein dimerization with hundreds of targets and wide-ranging cellular functions. Despite its important roles, DYNLL1's own regulation remains poorly understood. Here we identify ASCIZ (ATMIN/ZNF822), an essential Zn2+ finger protein with dual roles in the DNA base damage response and as a developmental transcription factor, as a conserved regulator of Dynll1 gene expression. DYNLL1 levels are reduced by similar to 10-fold in the absence of ASCIZ in human, mouse and chicken cells. ASCIZ binds directly to the Dynll1 promoter and regulates its activity in a Zn2+ finger-dependent manner. DYNLL1 protein in turn interacts with ten binding sites in the ASCIZ transcription activation domain, and high DYNLL1 levels inhibit the transcriptional activity of ASCIZ. In addition, DYNLL1 was also required for DNA damage-induced ASCIZ focus formation. The dual ability of ASCIZ to activate Dynll1 gene expression and to sense free DYNLL1 protein levels enables a simple dynamic feedback loop to adjust DYNLL1 levels to cellular needs. The ASCIZ-DYNLL1 feedback loop represents a novel mechanism for auto-regulation of gene expression, where the gene product directly inhibits the transcriptional activator while bound at its own promoter.