Cyclin E deregulation promotes loss of specific genomic regions.
Cyclin E deregulation promotes loss of specific genomic regions.
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DOI：
10.1016/j.cub.2015.03.022
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发表时间：
2015-05-18
期刊：
影响因子：
9.2
通讯作者：
Reed, Steven I.
中科院分区：
文献类型：
--
作者：
Teixeira, Leonardo K.;Wang, Xianlong;Li, Yongjiang;Ekholm-Reed, Susanna;Wu, Xiaohua;Wang, Pei;Reed, Steven I.
细胞周期进程由蛋白激酶的细胞周期蛋白依赖性激酶 (Cdk) 家族调节，之所以如此命名是因为它们的激活取决于与称为细胞周期蛋白的调节亚基的关联。细胞周期蛋白 E 通常积聚在 G1/S 边界，通过激活 Cdk2 促进 S 期进入和进展。在正常细胞中，细胞周期蛋白 E/Cdk2 活性与 DNA 复制相关功能相关。然而，细胞周期蛋白 E 的失调会导致复制前复合物组装效率低下、复制应激和染色体不稳定。在恶性细胞中，细胞周期蛋白 E 经常过度表达，与乳腺癌患者的生存率降低相关。乳腺上皮细胞中细胞周期蛋白 E 失调的转基因小鼠会患上癌症，这证实了细胞周期蛋白 E 是一种癌蛋白。然而，细胞周期蛋白 E 介导的复制应激如何促进癌发生过程中的基因组不稳定仍不清楚。在这里，我们发现细胞周期蛋白 E 的失调会导致人乳腺上皮细胞进入有丝分裂，在少数特定位点产生短的未复制基因组片段，导致后期异常并最终缺失。不完全复制的区域优先位于复制晚期域、脆弱位点和断点，包括混合谱系白血病断点簇区域（MLL BCR）。此外，这些区域的特点是缺乏复制起点或不寻常的 DNA 结构。对大量乳腺肿瘤的分析表明，细胞周期蛋白 E 扩增与我们研究中确定的许多基因组位点的缺失之间存在显着相关性。我们的结果证明了癌基因诱导的复制应激如何导致人类癌症的基因组不稳定。
Cell cycle progression is regulated by the cyclin-dependent kinase (Cdk) family of protein kinases, so named because their activation depends on association with regulatory subunits known as cyclins. Cyclin E normally accumulates at the G1/S boundary, where it promotes S phase entry and progression by activating Cdk2. In normal cells, cyclin E/Cdk2 activity is associated with DNA replication-related functions. However, deregulation of cyclin E leads to inefficient assembly of pre-replication complexes, replication stress, and chromosome instability. In malignant cells, cyclin E is frequently overexpressed, correlating with decreased survival in breast cancer patients. Transgenic mice deregulated for cyclin E in the mammary epithelia develop carcinoma, confirming that cyclin E is an oncoprotein. However, it remains unknown how cyclin E-mediated replication stress promotes genomic instability during carcinogenesis. Here we show that deregulation of cyclin E causes human mammary epithelial cells to enter into mitosis with short unreplicated genomic segments at a small number of specific loci, leading to anaphase anomalies and ultimately deletions. Incompletely replicated regions are preferentially located at late-replicating domains, fragile sites and breakpoints, including the mixed-lineage leukemia breakpoint cluster region (MLL BCR). Furthermore, these regions are characterized by a paucity of replication origins or unusual DNA structures. Analysis of a large set of breast tumors shows a significant correlation between cyclin E amplification and deletions at a number of the genomic loci identified in our study. Our results demonstrate how oncogene-induced replication stress contributes to genomic instability in human cancer.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.5
作者：
Casper, AM;Nghiem, P;Glover, TW
通讯作者：
Glover, TW
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
DOI：
10.1083/jcb.201212058
发表时间：
2013-03-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Neelsen KJ;Zanini IM;Herrador R;Lopes M
通讯作者：
Lopes M