Potential conflict of interest: Nothing to report.
A novel role of nucleostemin in maintaining the genome integrity of dividing hepatocytes during mouse liver development and regeneration
Article first published online: 21 OCT 2013
Copyright © 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 6, pages 2176–2187, December 2013
How to Cite
Lin, T., Ibrahim, W., Peng, C.-Y., Finegold, M. J. and Tsai, R. Y.L. (2013), A novel role of nucleostemin in maintaining the genome integrity of dividing hepatocytes during mouse liver development and regeneration. Hepatology, 58: 2176–2187. doi: 10.1002/hep.26600
This work was supported, in part, by a Texas A&M Cancer Research Council Incentive Award (to R.Y.L.T.), a National Institutes of Health (NIH) grant (P30 DK56338) that supports the Texas Medical Center Digestive Diseases Center (to R.Y.L.T. and M.J.F.), and an Egyptian Cultural and Educational Bureau postdoctoral fellowship (to W.I.). The authors thank Dr. Valentina Factor (National Cancer Institute, NIH, Bethesda, MD) for providing A6 antibody.
- Issue published online: 26 NOV 2013
- Article first published online: 21 OCT 2013
- Accepted manuscript online: 28 JUN 2013 02:21PM EST
- Manuscript Accepted: 17 JUN 2013
- Manuscript Received: 4 APR 2013
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 (albNScko) mouse model. Livers of albNScko 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, albNScko livers develop bile duct hyperplasia and show increased apoptotic cells, necrosis, regenerative nodules, and evidence suggestive of hepatic stem/progenitor cell activation. CCl4 treatment enhances degeneration and DNA damage in NS-deleted hepatocytes and increases biliary hyperplasia and A6+ cells in albNScko livers. After 70% partial hepatectomy, albNScko 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. (Hepatology 2013; 58:2176–2187)