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受到抑制时，胆道上皮细胞（BECs）转分化为新生肝细胞以完成肝再生。尽管对转分化很感兴趣，但对新生肝细胞在受伤后环境中的维持知之甚少。在这里，我们进行了 N-乙基-N-亚硝基脲 (ENU) 正向遗传筛选，并鉴定了一个在nibrin ( nbn ) 基因中包含无义突变的突变体，该突变体编码 Mre11-Rad50-Nbn (MRN) 复合体的一个成分激活 DNA 损伤反应 (DDR)。再生的肝细胞不能维持并且在突变体中表现出细胞凋亡。从机制上讲，nbn突变导致新生肝细胞中 ATR-Chk1 信号的消除和 DNA 损伤的积累，最终诱导 p53 介导的细胞凋亡。此外，rad50或mre11a的丢失显示出相似的表型。这项研究揭示了 MRN 复合物对 DDR 的激活对于 BEC 衍生的肝细胞的存活至关重要，解决了如何在受伤后的环境中维持新生肝细胞的问题。