Document Detail


Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice.
MedLine Citation:
PMID:  10801416     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Checkpoints of DNA integrity are conserved throughout evolution, as are the kinases ATM (Ataxia Telangiectasia mutated) and ATR (Ataxia- and Rad-related), which are related to phosphatidylinositol (PI) 3-kinase [1] [2] [3]. The ATM gene is not essential, but mutations lead to ataxia telangiectasia (AT), a pleiotropic disorder characterised by radiation sensitivity and cellular checkpoint defects in response to ionising radiation [4] [5] [6]. The ATR gene has not been associated with human syndromes and, structurally, is more closely related to the canonical yeast checkpoint genes rad3(Sp) and MEC1(Sc) [7] [8]. ATR has been implicated in the response to ultraviolet (UV) radiation and blocks to DNA synthesis [8] [9] [10] [11], and may phosphorylate p53 [12] [13], suggesting that ATM and ATR may have similar and, perhaps, complementary roles in cell-cycle control after DNA damage. Here, we report that targeted inactivation of ATR in mice by disruption of the kinase domain leads to early embryonic lethality before embryonic day 8.5 (E8.5). Heterozygous mice were fertile and had no aberrant phenotype, despite a lower ATR mRNA level. No increase was observed in the sensitivity of ATR(+/-) embryonic stem (ES) cells to a variety of DNA-damaging agents. Attempts to target the remaining wild-type ATR allele in heterozygous ATR(+/-) ES cells failed, supporting the idea that loss of both alleles of the ATR gene, even at the ES-cell level, is lethal. Thus, in contrast to the closely related checkpoint gene ATM, ATR has an essential function in early mammalian development.
Authors:
A de Klein; M Muijtjens; R van Os; Y Verhoeven; B Smit; A M Carr; A R Lehmann; J H Hoeijmakers
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Current biology : CB     Volume:  10     ISSN:  0960-9822     ISO Abbreviation:  Curr. Biol.     Publication Date:  2000 Apr 
Date Detail:
Created Date:  2000-06-02     Completed Date:  2000-06-02     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  9107782     Medline TA:  Curr Biol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  479-82     Citation Subset:  IM    
Affiliation:
MGC Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus University, Rotterdam, The Netherlands. deklein@gen.fgg.eur.nl
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MeSH Terms
Descriptor/Qualifier:
Alleles
Animals
Cell Cycle Proteins / analysis,  genetics,  physiology*
Cell Line
Cells, Cultured
Chimera
Chromosomes / chemistry
DNA / radiation effects
DNA Damage
DNA-Binding Proteins
Embryo Loss*
Gamma Rays
Mice
Mitomycin / pharmacology
Protein-Serine-Threonine Kinases / analysis,  genetics
Stem Cells / cytology
Tumor Suppressor Proteins
Ultraviolet Rays
Chemical
Reg. No./Substance:
0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Tumor Suppressor Proteins; 50-07-7/Mitomycin; 9007-49-2/DNA; EC 2.7.1.-/Atr protein, mouse; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein

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