Fig. 7: The molecular mechanism model showing the MRN complex governs the survival of regenerating hepatocytes in the later stage of liver regeneration.

During the highly proliferative phase of liver regeneration, the hepatocytes undergo endogenous DNA damage caused by replication stress. In normal livers, the MRN complex is recruited to DNA damage and activates ATM and ATR, subsequently triggering an intricate signal transduction network called DNA damage response. Activated cell cycle checkpoints arrest cell cycle progression and allow DNA repair so regenerated hepatocytes can survive and proliferate. In nbn mutant, the truncated Nbn mislocalizes in the cytoplasm, and the MRN complex cannot be recruited to the DNA damage site. The ATR-Chk1 signaling is prevented from activation. The stalled replication fork may collapse and trigger p53-dependent apoptosis, ultimately leading to defective liver regeneration.