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 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.
Lazzerini Denchi
Eros
E
Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10021, USA.
Celli
Giulia
G
de Lange
Titia
T
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D004249:DNA Damage; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008099:Liver / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D008115:Liver Regeneration / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53