| Human Embryonic Stem Cells Fail to Activate CHK1 and Commit to Apoptosis in Response to DNA Replication Stress. | |
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MedLine Citation:
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PMID: 22553144 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Pluripotent cells of the early embryo, to which embryonic stem (ES) cells 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 ES cells appears 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 ES cells and their malignant counterpart, embryonic carcinoma (EC) cells, both fail to activate critical S-phase checkpoints when exposed to DNA replication inhibitors and commit to apoptosis instead. Human ES and EC cells also fail to form RPA, γH2AX or RAD51 foci or load TOPBP1 onto chromatin in response to replication inhibitors. Furthermore direct measurements of ssDNA show that these cells fail to generate the single-stranded DNA 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. |
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Authors:
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Joëlle A Desmarais; Michele J Hoffmann; Gregg Bingham; Mary E Gagou; Mark Meuth; Peter W Andrews |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-5-2 |
Journal Detail:
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Title: Stem cells (Dayton, Ohio) Volume: - ISSN: 1549-4918 ISO Abbreviation: - Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-5-3 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9304532 Medline TA: Stem Cells Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 AlphaMed Press. |
Affiliation:
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Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Western Bank, Sheffield S10 2TN, UK; Institute for Cancer Studies, School of Medicine, The University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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