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The MRN complex maintains the biliary-derived hepatocytes in liver regeneration through ATR-Chk1 pathway.
Song, Jingmei; Ma, Jianlong; Liu, Xing; Huang, Zhuofu; Li, Lianghui; Li, Linke; Luo, Lingfei; Ni, Rui; He, Jianbo.
Affiliation
  • Song J; Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China.
  • Ma J; Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China.
  • Liu X; Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China.
  • Huang Z; Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China.
  • Li L; Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China.
  • Li L; Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China.
  • Luo L; Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China.
  • Ni R; Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China. nirui466@swu.edu.cn.
  • He J; Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China. hejianbo@swu.edu.cn.
NPJ Regen Med ; 8(1): 20, 2023 Apr 06.
Article de En | MEDLINE | ID: mdl-37024481
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.

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Langue: En Journal: NPJ Regen Med Année: 2023 Type de document: Article Pays d'affiliation: Chine Pays de publication: États-Unis d'Amérique

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Langue: En Journal: NPJ Regen Med Année: 2023 Type de document: Article Pays d'affiliation: Chine Pays de publication: États-Unis d'Amérique