A defective dNTP pool hinders DNA replication in cell cycle-reactivated terminally differentiated muscle cells

Deborah Pajalunga, Elisa Franzolin, Martina Stevanoni, Sara Zribi, Nunzia Passaro, Aymone Gurtner, Samantha Donsante, Daniela Loffredo, Lidia Losanno, Vera Bianchi, Antonella Russo, Chiara Rampazzo, Marco Crescenzi

Research output: Contribution to journalArticle

Abstract

Terminally differentiated cells are defined by their inability to proliferate. When forced to re-enter the cell cycle, they generally cannot undergo long-term replication. Our previous work with myotubes has shown that these cells fail to proliferate because of their intrinsic inability to complete DNA replication. Moreover, we have reported pronounced modifications of deoxynucleotide metabolism during myogenesis. Here we investigate the causes of incomplete DNA duplication in cell cycle-reactivated myotubes (rMt). We find that rMt possess extremely low levels of thymidine triphosphate (dTTP), resulting in very slow replication fork rates. Exogenous administration of thymidine or forced expression of thymidine kinase increases deoxynucleotide availability, allowing extended and faster DNA replication. Inadequate dTTP levels are caused by selective, differentiation-dependent, cell cycle-resistant suppression of genes encoding critical synthetic enzymes, chief among which is thymidine kinase 1. We conclude that lack of dTTP is at least partially responsible for the inability of myotubes to proliferate and speculate that it constitutes an emergency barrier against unwarranted DNA replication in terminally differentiated cells.

Original languageEnglish
Pages (from-to)774-784
Number of pages11
JournalCell Death and Differentiation
Volume24
Issue number5
DOIs
Publication statusPublished - May 1 2017

Keywords

  • cell cycle
  • Muscle cells
  • terminal differentiation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Pajalunga, D., Franzolin, E., Stevanoni, M., Zribi, S., Passaro, N., Gurtner, A., Donsante, S., Loffredo, D., Losanno, L., Bianchi, V., Russo, A., Rampazzo, C., & Crescenzi, M. (2017). A defective dNTP pool hinders DNA replication in cell cycle-reactivated terminally differentiated muscle cells. Cell Death and Differentiation, 24(5), 774-784. https://doi.org/10.1038/cdd.2017.4