Role of Cdc6 in re-replication in cells expressing human papillomavirus E7 oncogene
Role of Cdc6 in re-replication in cells expressing human papillomavirus E7 oncogene
复制标题
Cdc6 在表达人乳头瘤病毒 E7 癌基因的细胞再复制中的作用。
DOI：
10.1093/carcin/bgw059
复制
发表时间：
2016-08-01
期刊：
影响因子：
4.7
通讯作者：
Chen, Jason J.
中科院分区：
文献类型：
--
作者：
Fan, Xueli;Zhou, Yunying;Chen, Jason J.
高危型人乳头瘤病毒（HPV）的E7癌蛋白诱导DNA再复制，导致癌变;然而，其机制尚未完全了解。为了更好地理解E7诱导再复制的机制，我们研究了E7表达细胞中细胞分裂周期6（Cdc 6）的表达和功能。Cdc 6是一种DNA复制起始因子，当过表达时表现出致癌活性。我们发现，在E7表达细胞中，Cdc 6蛋白的稳态水平上调，其半衰期增加。Cdc 6定位于细胞核并与染色质相关，尤其是在DNA损伤时。重要的是，Cdc 6的下调减少了E7诱导的再复制。有趣的是，Cdc 6在丝氨酸54（S54 P）的磷酸化水平在E7表达细胞中增加。S54 P与Cdc 6和染色质结合Cdc 6总量的增加相关。DNA损伤增强上调和染色质结合的Cdc 6似乎是由于下调细胞周期蛋白依赖性激酶1（Cdk 1）的Cdk 1敲低增加Cdc 6水平。此外，Cdk 1敲低或抑制导致重新复制。这些发现揭示了HPV诱导基因组不稳定性的机制，并可能有助于确定药物开发的潜在靶点。
The E7 oncoprotein of high-risk human papillomavirus (HPV) types induces DNA re-replication that contributes to carcinogenesis; however, the mechanism is not fully understood. To better understand the mechanism by which E7 induces re-replication, we investigated the expression and function of cell division cycle 6 (Cdc6) in E7-expressing cells. Cdc6 is a DNA replication initiation factor and exhibits oncogenic activities when overexpressed. We found that in E7-expressing cells, the steady-state level of Cdc6 protein was upregulated and its half-life was increased. Cdc6 was localized to the nucleus and associated with chromatin, especially upon DNA damage. Importantly, downregulation of Cdc6 reduced E7-induced re-replication. Interestingly, the level of Cdc6 phosphorylation at serine 54 (S54P) was increased in E7-expressing cells. S54P was associated with an increase in the total amount of Cdc6 and chromatin-bound Cdc6. DNA damage-enhanced upregulation and chromatin binding of Cdc6 appeared to be due to downregulation of cyclin-dependent kinase 1 (Cdk1) as Cdk1 knockdown increased Cdc6 levels. Furthermore, Cdk1 knockdown or inhibition led to re-replication. These findings shed light on the mechanism by which HPV induces genomic instability and may help identify potential targets for drug development.