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A novel role of nucleostemin in maintaining the genome integrity of dividing hepatocytes during mouse liver development and regeneration
Author(s) -
Lin Tao,
Ibrahim Wessam,
Peng ChengYuan,
Finegold Milton J.,
Tsai Robert Y.L.
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26600
Subject(s) - dna damage , biology , dna repair , liver regeneration , progenitor cell , microbiology and biotechnology , proliferating cell nuclear antigen , dna replication , regeneration (biology) , rad51 , stem cell , cell growth , cancer research , dna , genetics
During liver development and regeneration, hepatocytes undergo rapid cell division and face an increased risk of DNA damage associated with active DNA replication. The mechanism that protects proliferating hepatocytes from replication‐induced DNA damage remains unclear. Nucleostemin (NS) is known to be up‐regulated during liver regeneration, and loss of NS is associated with increased DNA damage in cancer cells. To determine whether NS is involved in protecting the genome integrity of proliferating hepatocytes, we created an albumin promoter‐driven NS conditional‐null (albNS cko ) mouse model. Livers of albNS cko mice begin to show loss of NS in developing hepatocytes from the first postnatal week and increased DNA damage and hepatocellular injury at 1‐2 weeks of age. At 3‐4 weeks, albNS cko livers develop bile duct hyperplasia and show increased apoptotic cells, necrosis, regenerative nodules, and evidence suggestive of hepatic stem/progenitor cell activation. CCl 4 treatment enhances degeneration and DNA damage in NS‐deleted hepatocytes and increases biliary hyperplasia and A6 + cells in albNS cko livers. After 70% partial hepatectomy, albNS cko livers show increased DNA damage in parallel with a blunted and prolonged regenerative response. The DNA damage in NS‐depleted hepatocytes is explained by the impaired recruitment of a core DNA repair enzyme, RAD51, to replication‐induced DNA damage foci. Conclusion : This work reveals a novel genome‐protective role of NS in developing and regenerating hepatocytes. (H epatology 2013; 58:2176–2187)