ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage

Mirit I. Aladjem, Benjamin T. Spike, Luo Wei Rodewald, Thomas J. Hope, Martina Klemm, Rudolf Jaenisch, Geoffrey M. Wahl*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

359 Scopus citations

Abstract

Background: Embryonic stem (ES) cells can contribute precursors to all adult cell lineages. Consequently, damage to ES cell genomes may cause serious developmental malfunctions. In somatic cells, cell-cycle checkpoints limit DNA damage of preventing DNA replication under conditions that may produce chromosomal aberrations. The tumor suppressor p53 is involved in such checkpoint controls and is also required to avoid a high rate of embryonic malformations. We characterized the cell-cycle and DNA-damage responses of ES cells to elucidate the mechanisms that prevent accumulation or transmission of damaged genomes during development. Results: ES cells derived from wild-type mice did not undergo cell-cycle arrest in response to DNA damage or nucleotide depletion, although they synthesized abundant quantities of p53. The p53 protein in ES cells was cytoplasmic and translocated inefficiently to the nucleus upon nucleotide depletion. Expression of high level of active p53 from an adenovirus sector could not trigger cell-cycle arrest. Instead, ES cells that sustained DNA damage underwent p53-independent apoptosis. The antimetabolite-induced p53-dependent arrest response was restored in ES cells upon differentiation. Conclusions: Cell-cycle regulatory pathways in early embryos differ significantly from those in differentiated somatic cells. In undifferentiated ES cells, p53 checkpoint pathways are compromised by factors that affect the nuclear localization of p53 and by the loss of downstream factors that are necessary to induce cell-cycle arrest. A p53-independent programmed cell death pathway is effectively employed to prevent cells with damaged genomes from contributing to the developing organism. The p53-mediated checkpoint controls become important when differentiation occurs.

Original languageEnglish (US)
Pages (from-to)145-155
Number of pages11
JournalCurrent Biology
Volume8
Issue number3
DOIs
StatePublished - Jan 29 1998

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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