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J Mol Biol. 2017 Sep 1;429(18):2802-2815. doi: 10.1016/j.jmb.2017.06.020. Epub 2017 Jul 3.

Inhibition of Cell Division and DNA Replication Impair Mouse-Naïve Pluripotency Exit.

Author information

1
Universidad de Buenos Aires, Laboratorio de Regulación Génica en Células Madre, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Química Biológica (IQUIBICEN), Buenos Aires, Argentina.
2
Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY 10065, USA.
3
Universidad de Buenos Aires, Laboratorio de Regulación Génica en Células Madre, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
4
CONICET-Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI), Laboratorio de Investigación de Aplicación a Neurociencias (LIAN), Buenos Aires, Argentina.
5
Universidad de Buenos Aires, Laboratorio de Regulación Génica en Células Madre, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina; CONICET-Universidad de Buenos Aires, Instituto de Química Biológica (IQUIBICEN), Buenos Aires, Argentina; Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: algub@qb.fcen.uba.ar.

Abstract

The cell cycle has gained attention as a key determinant for cell fate decisions, but the contribution of DNA replication and mitosis in stem cell differentiation has not been extensively studied. To understand if these processes act as "windows of opportunity" for changes in cell identity, we established synchronized cultures of mouse embryonic stem cells as they exit the ground state of pluripotency. We show that initial transcriptional changes in this transition do not require passage through mitosis and that conversion to primed pluripotency is linked to lineage priming in the G1 phase. Importantly, we demonstrate that impairment of DNA replication severely blocks transcriptional switch to primed pluripotency, even in the absence of p53 activity induced by the DNA damage response. Our data suggest an important role for DNA replication during mouse embryonic stem cell differentiation, which could shed light on why pluripotent cells are only receptive to differentiation signals during G1, that is, before the S phase.

KEYWORDS:

DNA replication; cell division; mouse embryonic stem cells introduction; primitive ectoderm-like cells

PMID:
28684247
DOI:
10.1016/j.jmb.2017.06.020
[Indexed for MEDLINE]

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