Song Jingmei, Ma Jianlong, Liu Xing, Huang Zhuofu, Li Lianghui, Li Linke, Luo Lingfei, Ni Rui, He Jianbo
Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China.
NPJ Regen Med. 2023 Apr 6;8(1):20. doi: 10.1038/s41536-023-00294-3.
When the proliferation of residual hepatocytes is prohibited, biliary epithelial cells (BECs) transdifferentiate into nascent hepatocytes to accomplish liver regeneration. Despite significant interest in transdifferentiation, little is known about the maintenance of nascent hepatocytes in post-injured environments. Here, we perform an N-ethyl-N-nitrosourea (ENU) forward genetic screen and identify a mutant containing a nonsense mutation in the gene nibrin (nbn), which encodes a component of the Mre11-Rad50-Nbn (MRN) complex that activates DNA damage response (DDR). The regenerated hepatocytes cannot be maintained and exhibit apoptosis in the mutant. Mechanistically, the nbn mutation results in the abrogation of ATR-Chk1 signaling and accumulations of DNA damage in nascent hepatocytes, which eventually induces p53-mediated apoptosis. Furthermore, loss of rad50 or mre11a shows similar phenotypes. This study reveals that the activation of DDR by the MRN complex is essential for the survival of BEC-derived hepatocytes, addressing how to maintain nascent hepatocytes in the post-injured environments.
当残余肝细胞的增殖被抑制时，胆管上皮细胞（BECs）会转分化为新生肝细胞以完成肝脏再生。尽管对转分化有浓厚兴趣，但对于损伤后环境中新生肝细胞的维持机制却知之甚少。在此，我们进行了N-乙基-N-亚硝基脲（ENU）正向遗传学筛选，鉴定出一个在nibrin（nbn）基因中含有无义突变的突变体，该基因编码激活DNA损伤反应（DDR）的Mre11-Rad50-Nbn（MRN）复合物的一个组分。再生肝细胞在该突变体中无法维持并发生凋亡。从机制上讲，nbn突变导致ATR-Chk1信号通路的废除以及新生肝细胞中DNA损伤的积累，最终诱导p53介导的凋亡。此外，rad50或mre11a的缺失表现出相似的表型。这项研究揭示了MRN复合物激活DDR对于BEC来源的肝细胞存活至关重要，为如何在损伤后环境中维持新生肝细胞提供了解答。
