Document Detail


Protecting genomic integrity in somatic cells and embryonic stem cells.
MedLine Citation:
PMID:  16914171     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mutation frequencies at some loci in mammalian somatic cells in vivo approach 10(-4). The majority of these events occur as a consequence of loss of heterozygosity (LOH) due to mitotic recombination. Such high levels of DNA damage in somatic cells, which can accumulate with age, will cause injury and, after a latency period, may lead to somatic disease and ultimately death. This high level of DNA damage is untenable for germ cells, and by extrapolation for embryonic stem (ES) cells, that must recreate the organism. ES cells cannot tolerate such a high frequency of damage since mutations will immediately impact the altered cell, and subsequently the entire organism. Most importantly, the mutations may be passed on to future generations. ES cells, therefore, must have robust mechanisms to protect the integrity of their genomes. We have examined two such mechanisms. Firstly, we have shown that mutation frequencies and frequencies of mitotic recombination in ES cells are about 100-fold lower than in adult somatic cells or in isogenic mouse embryonic fibroblasts (MEFs). A second complementary protective mechanism eliminates those ES cells that have acquired a mutational burden, thereby maintaining a pristine population. Consistent with this hypothesis, ES cells lack a G1 checkpoint, and the two known signaling pathways that mediate the checkpoint are compromised. The checkpoint kinase, Chk2, which participates in both pathways is sequestered at centrosomes in ES cells and does not phosphorylate its substrates (i.e. p53 and Cdc25A) that must be modified to produce a G1 arrest. Ectopic expression of Chk2 does not rescue the p53-mediated pathway, but does restore the pathway mediated by Cdc25A. Wild type ES cells exposed to ionizing radiation do not accumulate in G1 but do so in S-phase and in G2. ES cells that ectopically express Chk2 undergo cell cycle arrest in G1 as well as G2, and appear to be protected from apoptosis.
Authors:
Y Hong; R B Cervantes; E Tichy; J A Tischfield; P J Stambrook
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Review     Date:  2006-08-17
Journal Detail:
Title:  Mutation research     Volume:  614     ISSN:  0027-5107     ISO Abbreviation:  Mutat. Res.     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2006-12-20     Completed Date:  2007-02-09     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  0400763     Medline TA:  Mutat Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  48-55     Citation Subset:  IM    
Affiliation:
Department of Cell biology, Neurobiology and Anatomy, University of Cincinnati Medical Center, 3125 Eden Avenue, Cincinnati, OH 45267-0521, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenine Phosphoribosyltransferase / deficiency,  genetics
Animals
DNA Damage
DNA Repair
Embryonic Stem Cells / metabolism*,  radiation effects
Genome
Mice
Mice, Knockout
Models, Genetic
Mutation*
Protein-Serine-Threonine Kinases / genetics,  metabolism
Recombination, Genetic
Signal Transduction
Transfection
Grant Support
ID/Acronym/Agency:
P30-ES06096/ES/NIEHS NIH HHS; R01-CA90934/CA/NCI NIH HHS; T32 ES07250/ES/NIEHS NIH HHS; U01-ES11038/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
EC 2.4.2.7/Adenine Phosphoribosyltransferase; EC 2.7.1.11/checkpoint kinase 2; EC 2.7.11.1/Protein-Serine-Threonine Kinases

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


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