Journal
JOURNAL OF CELL BIOLOGY
Volume 213, Issue 5, Pages 571-583Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201510091
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Funding
- Formation de Profesorado Universitario predoctoral fellowship from the Ministerio de Educacion
- Ministerio de Economia y Competitividad
- Fundacion Cientifica Asociacion Espanola Contra el Cancer postdoctoral fellowship
- Red Tematica de Investigation Cooperativa en Enfermedades Cardiovasculares [RD12/0042/0045]
- Pro-CNIC Foundation
- Severo Ochoa Center of Excellence (Ministerio de Economia y Competitividad) [SEV-2015-0505]
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The molecular mechanisms that drive mammalian cardiomyocytes out of the cell cycle soon after birth remain largely unknown. Here, we identify telomere dysfunction as a critical physiological signal for cardiomyocyte cell-cycle arrest. We show that telomerase activity and cardiomyocyte telomere length decrease sharply in wild-type mouse hearts after birth, resulting in cardiomyocytes with dysfunctional telomeres and anaphase bridges and positive for the cell-cycle arrest protein p21. We further show that premature telomere dysfunction pushes cardiomyocytes out of the cell cycle. Cardiomyocytes from telomerase-deficient mice with dysfunctional telomeres (G3 Terc(-/-)) show precocious development of anaphase-bridge formation, p21 up-regulation, and binucleation. In line with these findings, the cardiomyocyte proliferative response after cardiac injury was lost in G3 Terc(-/-) newborns but rescued in G3 Terc(-/-)/p21(-/-) mice. These results reveal telomere dysfunction as a crucial signal for cardiomyocyte cell-cycle arrest after birth and suggest interventions to augment the regeneration capacity of mammalian hearts.
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