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首页> 外文期刊>Molecular and Cellular Biology >The Xeroderma Pigmentosum Group E Gene Product DDB2 Is a Specific Target of Cullin 4A in Mammalian Cells
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The Xeroderma Pigmentosum Group E Gene Product DDB2 Is a Specific Target of Cullin 4A in Mammalian Cells

机译：Xeroderma Pigmentosum E组基因产物DDB2是哺乳动物细胞中Cullin 4A的特异性靶标

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The damaged-DNA binding protein DDB consists of two subunits, DDB1 (127 kDa) and DDB2 (48 kDa). Mutations in the DDB2 subunit have been detected in patients suffering from the repair deficiency disease xeroderma pigmentosum (group E). In addition, recent studies suggested a role for DDB2 in global genomic repair. DDB2 also exhibits transcriptional activity. We showed that expression of DDB1 and DDB2 stimulated the activity of the cell cycle regulatory transcription factor E2F1. Here we show that DDB2 is a cell cycle-regulated protein. It is present at a low level in growth-arrested primary fibroblasts, and after release the level peaks at the G1/S boundary. The cell cycle regulation of DDB2 involves posttranscriptional mechanisms. Moreover, we find that an inhibitor of 26S proteasome increases the level of DDB2, suggesting that it is regulated by the ubiquitin-proteasome pathway. Our previous study indicated that the cullin family protein Cul-4A associates with the DDB2 subunit. Because cullins are involved in the ubiquitin-proteasome pathway, we investigated the role of Cul-4A in regulating DDB2. Here we show that DDB2 is a specific target of Cul-4A. Coexpression of Cul-4A, but not Cul-1 or other highly related cullins, increases the ubiquitination and the decay rate of DDB2. A naturally occurring mutant of DDB2 (2RO), which does not bind Cul-4A, is not affected by coexpression of Cul-4A. Studies presented here identify a specific function of the Cul-4A gene, which is amplified and overexpressed in breast cancers.
机译：受损的DNA结合蛋白DDB由两个亚基DDB1（127 kDa）和DDB2（48 kDa）组成。在患有缺损修复性皮肤干燥性皮肤病（E组）的患者中检测到DDB2亚基的突变。此外，最近的研究表明DDB2在全球基因组修复中的作用。 DDB2还表现出转录活性。我们表明DDB1和DDB2的表达刺激细胞周期调节转录因子E2F1的活动。在这里，我们显示DDB2是一种细胞周期调节蛋白。它在生长停滞的原代成纤维细胞中以较低的水平存在，释放后在G 1 / S边界的水平达到峰值。 DDB2的细胞周期调控涉及转录后机制。此外，我们发现26S蛋白酶体的抑制剂会增加DDB2的水平，表明它受泛素-蛋白酶体途径的调节。我们以前的研究表明，cullin家族蛋白Cul-4A与DDB2亚基相关。由于cullins参与了泛素-蛋白酶体途径，因此我们研究了Cul-4A在调节DDB2中的作用。在这里，我们显示DDB2是Cul-4A的特定靶标。 Cul-4A而不是Cul-1或其他高度相关的cullins的共表达增加了DDB2的泛素化和衰减率。不结合Cul-4A的DDB2（2RO）天然突变体不受Cul-4A共表达的影响。本文介绍的研究确定了Cul-4A基因的特定功能，该基因在乳腺癌中被扩增和过表达。

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