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Cell Res:中科院昆明动物所郑萍课题组发表多能干细胞遗传物质稳定性调控研究论文

摘要 : 2017年11月10日,国际学术权威刊物自然出版集团旗下子刊《Cell Research》杂志在线发表了中国科学院昆明动物研究所郑萍课题组在多能干细胞遗传物质稳定性调控研究中的进展

2017年11月10日,国际学术权威刊物自然出版集团旗下子刊《Cell Research》杂志在线发表了中国科学院昆明动物研究所郑萍课题组在多能干细胞遗传物质稳定性调控研究中的进展,研究论文题为“Mouse embryonic stem cells have increased capacity for replication fork restart driven by the specific Filia-Floped protein complex”。研究工作首次揭示了多能干细胞以独特的机制高效处理DNA复制压力,从而在快速分裂中有效维持遗传物质稳定性。郑萍课题组的副研究员赵博及博士研究生张伟道为本文的共同第一作者,郑萍研究员为通讯作者。

干细胞在再生医学中的应用前景巨大,遗传物质稳定是其安全应用的前提。和分化细胞相比,干细胞的细胞周期短,DNA复制频繁,且细胞周期中G1期十分短暂,也缺乏G1细胞周期检查点,这些特征使得干细胞在DNA复制中面临巨大的复制压力。复制压力是内源性DNA损伤和基因组不稳定的主要来源,有效处理复制压力是细胞维持遗传物质稳定性的重要途径。但目前尚不清楚干细胞如何有效处理复制压力。

郑萍课题组研究了多能干细胞对DNA复制压力的处理能力及分子机制。通过系统比较小鼠胚胎干细胞和不同类型的快速分裂的分化细胞,发现多能干细胞具有高效的复制压力处理能力,能有效重启受阻复制叉,并找到了调控复制叉高效重启的干细胞特有的蛋白复合体Filia-Floped,阐述了其作用机制。具体讲,Filia和Floped形成蛋白复合体,常态性结合在复制叉上。当复制叉受阻时, Filia-Floped蛋白复合物大量聚集到受阻复制叉上,并在蛋白激酶ATR(调控复制压力反应的核心激酶)的调控下,Filia的第151位丝氨酸发生磷酸化,使Filia-Floped复合体形成有功能的脚手架。该脚手架进而通过两条独立的途径高效调控复制叉重启。一方面,脚手架蛋白招募E3 泛素化酶Trim25到受阻复制叉上,Trim25通过催化其底物Blm(促进复制叉重启的关键解旋酶)发生泛素化修饰,从而招募大量的Blm到受阻复制叉上调控复制叉重启;另一方面,脚手架蛋白还能通过未知机制高效激活ATR激酶活性调控复制叉重启(图1)。因此,多能干细胞通过在复制叉上增添Filia-Floped脚手架,它以类似海绵的作用,迅速富集大量的复制叉维护和修复因子到受阻复制叉上,从而高效维持复制叉稳定和重启。

图. 复制叉上Filia-Floped蛋白复合体的作用模式图

原文链接:

Mouse embryonic stem cells have increased capacity for replication fork restart driven by the specific Filia-Floped protein complex

原文摘要:

Pluripotent stem cells (PSCs) harbor constitutive DNA replication stress during their rapid proliferation and the consequent genome instability hampers their applications in regenerative medicine. It is therefore important to understand the regulatory mechanisms of replication stress response in PSCs. Here, we report that mouse embryonic stem cells (ESCs) are superior to differentiated cells in resolving replication stress. Specifically, ESCs utilize a unique Filia-Floped protein complex-dependent mechanism to efficiently promote the restart of stalled replication forks, therefore maintaining genomic stability. The ESC-specific Filia-Floped complex resides on replication forks under normal conditions. Replication stress stimulates their recruitment to stalling forks and the serine 151 residue of Filia is phosphorylated in an ATR-dependent manner. This modification enables the Filia-Floped complex to act as a functional scaffold, which then promotes the stalling fork restart through a dual mechanism: both enhancing recruitment of the replication fork restart protein, Blm, and stimulating ATR kinase activation. In the Blm pathway, the scaffolds recruit the E3 ubiquitin ligase, Trim25, to the stalled replication forks, and in turn Trim25 tethers and concentrates Blm at stalled replication forks through ubiquitination. In differentiated cells, the recruitment of the Trim25-Blm complex to replication forks and the activation of ATR signaling are much less robust due to lack of the ESC-specific Filia-Floped scaffold. Thus, our study reveals that ESCs utilize an additional and unique regulatory layer to efficiently promote the stalled fork restart and maintain genomic stability.

来源: Cell Research 浏览次数:0

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