mouseembryonicstemcellshaveincreasedcapacityforreplicationforkrestartdrivenbythespecificfiliaflopedproteincomplex

doi:10.1038/cr.2017.139

	mouseembryonicstemcellshaveincreasedcapacityforreplicationforkrestartdrivenbythespecificfiliaflopedproteincomplex
	Zhao Bo 1; Zhang Weidao 1; Cun Yixian 1; Li Jingzheng 1; Liu Yan 1; Gao Jing 2; Zhu Hongwen 2; Zhou Hu 2; Zhang Rugang 3; Zheng Ping 1
刊名	cellresearch
	2018
卷号	28 期号:1 页码:69
关键词	pluripotent stem cells Filia Floped DNA replication stress genomic stability
ISSN号	1001-0602
DOI	10.1038/cr.2017.139
英文摘要	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.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/286826]
专题	中国科学院上海药物研究所
作者单位	1.中国科学院动物研究所 2.中国科学院上海药物研究所 3.Gene Expression and Regulation Program, The Wistar Institute Cancer Center, The Wistar Institute
推荐引用方式 GB/T 7714	Zhao Bo,Zhang Weidao,Cun Yixian,et al. mouseembryonicstemcellshaveincreasedcapacityforreplicationforkrestartdrivenbythespecificfiliaflopedproteincomplex[J]. cellresearch,2018,28(1):69.
APA	Zhao Bo.,Zhang Weidao.,Cun Yixian.,Li Jingzheng.,Liu Yan.,...&Zheng Ping.(2018).mouseembryonicstemcellshaveincreasedcapacityforreplicationforkrestartdrivenbythespecificfiliaflopedproteincomplex.cellresearch,28(1),69.
MLA	Zhao Bo,et al."mouseembryonicstemcellshaveincreasedcapacityforreplicationforkrestartdrivenbythespecificfiliaflopedproteincomplex".cellresearch 28.1(2018):69.