Document Detail


Human embryonic stem cells fail to activate CHK1 and commit to apoptosis in response to DNA replication stress.
MedLine Citation:
PMID:  22553144     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pluripotent cells of the early embryo, to which embryonic stem cells (ESCs) correspond, give rise to all the somatic cells of the developing fetus. Any defects that occur in their genome or epigenome would have devastating consequences. Genetic and epigenetic change in human ESCs appear to be an inevitable consequence of long-term culture, driven by selection of variant cells that have a higher propensity for self-renewal rather than either differentiation or death. Mechanisms underlying the potentially separate events of mutation and subsequent selection of variants are poorly understood. Here, we show that human ESCs and their malignant counterpart, embryonal carcinoma (EC) cells, both fail to activate critical S-phase checkpoints when exposed to DNA replication inhibitors and commit to apoptosis instead. Human ESCs and EC cells also fail to form replication protein A, γH2AX, or RAD51 foci or load topoisomerase (DNA) II binding protein 1 onto chromatin in response to replication inhibitors. Furthermore, direct measurements of single-stranded DNA (ssDNA) show that these cells fail to generate the ssDNA regions in response to replication stress that are necessary for the activation of checkpoints and the initiation of homologous recombination repair to protect replication fork integrity and restart DNA replication. Taken together, our data suggest that pluripotent cells control genome integrity by the elimination of damaged cells through apoptosis rather than DNA repair, and therefore, mutations or epigenetic modifications resulting in an imbalance in cell death control could lead to genetic instability.
Authors:
Joëlle A Desmarais; Michele J Hoffmann; Gregg Bingham; Mary E Gagou; Mark Meuth; Peter W Andrews
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Stem cells (Dayton, Ohio)     Volume:  30     ISSN:  1549-4918     ISO Abbreviation:  Stem Cells     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-20     Completed Date:  2012-10-19     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  9304532     Medline TA:  Stem Cells     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1385-93     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 AlphaMed Press.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / genetics,  physiology
Cell Cycle / genetics,  physiology
Cell Line
Chromosome Aberrations
DNA Repair / genetics*
DNA Replication / genetics
Embryonic Stem Cells / metabolism*
Fluorescent Antibody Technique
Genetic Variation / genetics
Humans
Immunoblotting
Protein Kinases / metabolism*
Grant Support
ID/Acronym/Agency:
G0700785//Medical Research Council; //Medical Research Council
Chemical
Reg. No./Substance:
EC 2.7.-/Protein Kinases; EC 2.7.11.1/Checkpoint kinase 1

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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