2017年11月10日, 國際學術權威刊物自然出版集團旗下子刊《Cell Research》雜誌線上發表了中國科學院昆明動物研究所鄭萍課題組在多能幹細胞遺傳物質穩定性調控研究中的進展, 研究論文題為“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幹細胞以獨特的機制高效處理DNA複製壓力, 從而在快速分裂中有效維持遺傳物質穩定性。 鄭萍課題組的副研究員趙博及博士研究生張偉道為本文的共同第一作者, 鄭萍研究員為通訊作者。
幹細胞在再生醫學中的應用前景巨大, 遺傳物質穩定是其安全應用的前提。 和分化細胞相比, 幹細胞的細胞週期短,
鄭萍課題組研究了多能幹細胞對DNA複製壓力的處理能力及分子機制。 通過系統比較小鼠胚胎幹細胞和不同類型的快速分裂的分化細胞, 發現多能幹細胞具有高效的複製壓力處理能力, 能有效重啟受阻複製叉, 並找到了調控複製叉高效重啟的幹細胞特有的蛋白複合體Filia-Floped, 闡述了其作用機制。 具體講, Filia和Floped形成蛋白複合體,
圖. 複製叉上Filia-Floped蛋白複合體的作用模式圖
原文連結:
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.