Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice
| Autor: | R. van Os, Manja Muijtjens, Antony M. Carr, J.H.J. Hoeijmakers, Alan R. Lehmann, Bep Smit, A. de Klein, Y. Verhoeven |
|---|---|
| Přispěvatelé: | Molecular Genetics |
| Rok vydání: | 2000 |
| Předmět: |
Ultraviolet Rays
DNA damage Mitomycin Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Biology Chromosomes General Biochemistry Genetics and Molecular Biology Cell Line Mice medicine Animals CHEK1 Alleles Cells Cultured DNA-PKcs Agricultural and Biological Sciences(all) Chimera Biochemistry Genetics and Molecular Biology(all) Stem Cells Tumor Suppressor Proteins DNA G2-M DNA damage checkpoint Cell cycle medicine.disease Molecular biology DNA-Binding Proteins Protein kinase domain Gamma Rays Ataxia-telangiectasia Embryo Loss biological phenomena cell phenomena and immunity General Agricultural and Biological Sciences Ataxia telangiectasia and Rad3 related DNA Damage |
| Zdroj: | Current Biology, 10(8), 479-482. Cell Press |
| ISSN: | 0960-9822 |
| DOI: | 10.1016/s0960-9822(00)00447-4 |
| Popis: | 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 [1–3]. 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 [4–6]. 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 [8–11], 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. |
| Databáze: | OpenAIRE |
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