DNA replication is intrinsically hindered in terminally differentiated myotubes.

PloS One
Deborah PajalungaMarco Crescenzi

Abstract

Terminally differentiated (TD) cells permanently exit the mitotic cycle while acquiring specialized characteristics. Although TD cells can be forced to reenter the cell cycle by different means, they cannot be made to stably proliferate, as attempts to induce their replication constantly result in cell death or indefinite growth arrest. There is currently no biological explanation for this failure. Here we show that TD mouse myotubes, reactivated by depletion of the p21 and p27 cell cycle inhibitors, are unable to complete DNA replication and sustain heavy DNA damage, which triggers apoptosis or results in mitotic catastrophe. In striking contrast, quiescent, non-TD fibroblasts and myoblasts, reactivated in the same way, fully replicate their DNA, do not suffer DNA damage, and proliferate even in the absence of growth factors. Similar results are obtained when myotubes and fibroblasts are reactivated by forced expression of E1A or cyclin D1 and cdk4. We conclude that the inability of myotubes to complete DNA replication must be ascribed to peculiar features inherent in their TD state, rather than to the reactivation method. On reviewing the literature concerning reactivation of other TD cell types, we propose that similar mecha...Continue Reading

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Citations

Jul 7, 2011·PloS One·Janeth Alva-MedinaArmando Aranda-Anzaldo
Jan 12, 2012·PloS One·Nikolaos P MastroyiannopoulosLeonidas A Phylactou
Nov 6, 2013·Bioscience Reports·Nikolaos P MastroyiannopoulosLeonidas A Phylactou
Feb 12, 2015·Molecular Therapy : the Journal of the American Society of Gene Therapy·Maria Grazia BiferiMarco Crescenzi
Jul 19, 2012·Communicative & Integrative Biology·Armando Aranda-Anzaldo
Oct 11, 2013·Cell Cycle·Alessandra AlteriMilena Grossi
Feb 12, 2017·Cell Death and Differentiation·Deborah PajalungaMarco Crescenzi
Oct 18, 2018·Stem Cells and Development·Amanda L PattersonJose M Teixeira
Sep 4, 2019·The Journal of Clinical Investigation·Raphael ScharfmannOlivier Albagli
Feb 8, 2011·Aging·Mikhail V Blagosklonny
Jul 13, 2016·Journal of Neuroscience Research·Armando Aranda-Anzaldo, Myrna A R Dent
Nov 30, 2020·Mechanisms of Ageing and Development·Lemuel A BrownTyrone A Washington

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Methods Mentioned

BETA
electrophoresis
transfection
FACS

Software Mentioned

IAS
Twist

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