Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication

We report that mouse liver cells are highly resistant to extensive telomere dysfunction. In proliferating cells, telomere dysfunction results in chromosome end fusions, a DNA damage signal, and apoptosis or senescence. To determine the consequences of telomere dysfunction in noncycling cells, we use...

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Bibliographic Details
Published in:Genes & development 2006-10, Vol.20 (19), p.2648-2653
Main Authors: Lazzerini Denchi, Eros, Celli, Giulia, de Lange, Titia
Format: Article
Language:English
Subjects:
Animals
Apoptosis - genetics
Apoptosis - physiology
Cell Proliferation
Cellular Senescence - genetics
Cellular Senescence - physiology
DNA Damage
Female
Hepatocytes - cytology
Hepatocytes - metabolism
In Situ Hybridization, Fluorescence - methods
Liver - pathology
Liver - physiopathology
Liver - surgery
Liver Regeneration - genetics
Liver Regeneration - physiology
Male
Mice
Mice, Knockout
Mice, Transgenic
Research Communication
Telomere - genetics
Telomere - metabolism
Telomeric Repeat Binding Protein 2 - genetics
Telomeric Repeat Binding Protein 2 - metabolism
Telomeric Repeat Binding Protein 2 - physiology
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:We report that mouse liver cells are highly resistant to extensive telomere dysfunction. In proliferating cells, telomere dysfunction results in chromosome end fusions, a DNA damage signal, and apoptosis or senescence. To determine the consequences of telomere dysfunction in noncycling cells, we used conditional deletion of the telomeric protein TRF2 in hepatocytes. TRF2 loss resulted in telomeric accumulation of gamma-H2AX and frequent telomere fusions, indicating telomere deprotection. However, there was no induction of p53 or apoptosis, and liver function appeared unaffected. Furthermore, the loss of TRF2 did not compromise liver regeneration after partial hepatectomy. Remarkably, liver regeneration occurred without cell division involving endoreduplication and cell growth, thereby circumventing the chromosome segregation problems associated with telomere fusions. We conclude that nondividing hepatocytes can maintain and regenerate liver function despite substantial loss of telomere integrity.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.1453606