Mouse embryonic stem cells have increased capacity for replication fork restart driven by the specific Filia-Floped protein complex
| Autor: | Jingzheng Li, Rugang Zhang, Yan Liu, Hongwen Zhu, Weidao Zhang, Yi-xian Cun, Bo Zhao, Ping Zheng, Jing Gao, Hu Zhou |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genome instability DNA Replication TRIM25 Cellular differentiation Ataxia Telangiectasia Mutated Proteins Genomic Instability 03 medical and health sciences Mice Ubiquitin Animals Phosphorylation Induced pluripotent stem cell Molecular Biology Genetics biology RecQ Helicases DNA replication Ubiquitination Proteins RNA-Binding Proteins Mouse Embryonic Stem Cells Cell Biology Embryonic stem cell Ubiquitin ligase Cell biology DNA-Binding Proteins 030104 developmental biology biology.protein NIH 3T3 Cells Original Article Transcription Factors |
| Zdroj: | Cell research. 28(1) |
| ISSN: | 1748-7838 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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