TY - JOUR
T1 - Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice
AU - De Klein, A.
AU - Muijtjens, M.
AU - Van Os, R.
AU - Verhoeven, Y.
AU - Smit, B.
AU - Carr, A. M.
AU - Lehmann, A. R.
AU - Hoeijmakers, J. H.J.
N1 - Funding Information:
This work was supported by grants from the Dutch Cancer Society (KWF 96-1297), the European Commission and The Netherlands Organization for Scientific Research (NWO-Spinoza). We thank D. Bootsma, I. vd Herik, B. vd Horst, M. Kuit, W. Muriel, M. Hoekstra and ICOS for support and R. Kanaar for comments on manuscript.
PY - 2000/4/1
Y1 - 2000/4/1
N2 - 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. 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. 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). ATR has been implicated in the response to ultraviolet (UV) radiation and blocks to DNA synthesis, and may phosphorylate p53, 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 bad 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.
AB - 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. 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. 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). ATR has been implicated in the response to ultraviolet (UV) radiation and blocks to DNA synthesis, and may phosphorylate p53, 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 bad 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.
UR - http://www.scopus.com/inward/record.url?scp=0034177408&partnerID=8YFLogxK
U2 - 10.1016/S0960-9822(00)00447-4
DO - 10.1016/S0960-9822(00)00447-4
M3 - Article
C2 - 10801416
AN - SCOPUS:0034177408
SN - 0960-9822
VL - 10
SP - 479
EP - 482
JO - Current Biology
JF - Current Biology
IS - 8
ER -