Home LiteratureArticle Details
PMID: 10691732 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

ATR disruption leads to chromosomal fragmentation and early embryonic lethality.

Genes & development ·Vol. 14 ·No. 4 ·2000-02-15 ·Pages 397-402

Brown EJ, Baltimore D

Abstract

Although a small decrease in survival and increase in tumor incidence was observed in ATR(+/-) mice, ATR(-/-) embryos die early in development, subsequent to the blastocyst stage and prior to 7.5 days p.c. In culture, ATR(-/-) blastocysts cells continue to cycle into mitosis for 2 days but subsequently fail to expand and die of caspase-dependent apoptosis. Importantly, caspase-independent chromosome breaks are observed in ATR(-/-) cells prior to widespread apoptosis, implying that apoptosis is caused by a loss of genomic integrity. These data show that ATR is essential for early embryonic development and must function in processes other than regulation of p53.

MeSH Terms
Animals Apoptosis/genetics Ataxia Telangiectasia Mutated Proteins BRCA1 Protein/physiology BRCA2 Protein Blastocyst/pathology Caspases/metabolism Cell Cycle Proteins Cell Transformation, Neoplastic/genetics Chromosome Aberrations DNA Repair/genetics Fetal Death/genetics Gene Expression Regulation, Developmental Gene Targeting Genotype Mice Mice, Inbred C57BL Mice, Knockout Mitosis Neoplasm Proteins/physiology Neoplasms, Experimental/genetics Protein Serine-Threonine Kinases/deficiency,genetics,physiology Transcription Factors/physiology
Chemicals
BRCA1 Protein BRCA2 Protein Cell Cycle Proteins Neoplasm Proteins Transcription Factors Atr protein, mouse Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Caspases
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Brown E J
California Institute of Technology, Division of Biology, Pasadena, California 91125 USA.
Baltimore D
References (36)
36 references, click to expand
  1. A role for ATR in the DNA damage-induced phosphorylation of p53.
    Genes Dev. 1999 Jan 15;13(2):152-7 PMID: 9925639
  2. 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage.
    Nature. 1999 Oct 7;401(6753):616-20 PMID: 10524633
  3. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells.
    Mol Cell. 1999 Mar;3(3):389-95 PMID: 10198641
  4. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks.
    Science. 1999 Nov 5;286(5442):1162-6 PMID: 10550055
  5. Caffeine-induced uncoupling of mitosis from the completion of DNA replication in mammalian cells.
    Science. 1986 Jun 6;232(4755):1264-6 PMID: 2422760
  6. Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated Cdc2 kinase.
    Cell. 1993 Aug 13;74(3):463-74 PMID: 8348613
  7. A mammalian protein targeted by G1-arresting rapamycin-receptor complex.
    Nature. 1994 Jun 30;369(6483):756-8 PMID: 8008069
  8. Tumor spectrum analysis in p53-mutant mice.
    Curr Biol. 1994 Jan 1;4(1):1-7 PMID: 7922305
  9. The p53-dependent G1 cell cycle checkpoint pathway and ataxia-telangiectasia.
    Cancer Res. 1994 Oct 1;54(19):5054-8 PMID: 7923116
  10. Mitotic checkpoint genes in budding yeast and the dependence of mitosis on DNA replication and repair.
    Genes Dev. 1994 Mar 15;8(6):652-65 PMID: 7926756
  11. The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene.
    Cell. 1995 Sep 8;82(5):815-21 PMID: 7671309
  12. TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1.
    Cell. 1995 Sep 8;82(5):831-40 PMID: 7545545
  13. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints.
    Science. 1995 Oct 6;270(5233):50-1 PMID: 7569949
  14. cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein.
    Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2850-5 PMID: 8610130
  15. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse.
    Cell. 1996 Jun 28;85(7):1009-23 PMID: 8674108
  16. Dual roles of ATM in the cellular response to radiation and in cell growth control.
    Genes Dev. 1996 Oct 1;10(19):2401-10 PMID: 8843193
  17. The Atr and Atm protein kinases associate with different sites along meiotically pairing chromosomes.
    Genes Dev. 1996 Oct 1;10(19):2423-37 PMID: 8843195
  18. A mutation in mouse rad51 results in an early embryonic lethal that is suppressed by a mutation in p53.
    Mol Cell Biol. 1996 Dec;16(12):7133-43 PMID: 8943369
  19. The Schizosaccharomyces pombe rad3 checkpoint gene.
    EMBO J. 1996 Dec 2;15(23):6641-51 PMID: 8978690
  20. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2.
    Nature. 1997 Apr 24;386(6627):804-10 PMID: 9126738
  21. Brca2 is required for embryonic cellular proliferation in the mouse.
    Genes Dev. 1997 May 15;11(10):1242-52 PMID: 9171369
  22. Caspase activity is required for commitment to Fas-mediated apoptosis.
    EMBO J. 1997 Jul 1;16(13):3805-12 PMID: 9233790
  23. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage.
    Cell. 1997 Aug 8;90(3):425-35 PMID: 9267023
  24. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints.
    EMBO J. 1998 Jan 2;17(1):159-69 PMID: 9427750
  25. ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage.
    Curr Biol. 1998 Jan 29;8(3):145-55 PMID: 9443911
  26. Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes.
    Genes Dev. 1998 Mar 15;12(6):806-19 PMID: 9512515
  27. Protein kinase mutants of human ATR increase sensitivity to UV and ionizing radiation and abrogate cell cycle checkpoint control.
    Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7445-50 PMID: 9636169
  28. Involvement of Brca2 in DNA repair.
    Mol Cell. 1998 Feb;1(3):347-57 PMID: 9660919
  29. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.
    Science. 1998 Sep 11;281(5383):1677-9 PMID: 9733515
  30. DNA damage and checkpoint pathways: molecular anatomy and interactions with repair.
    Cell. 1998 Sep 4;94(5):555-8 PMID: 9741620
  31. Checkpoints on the road to mitosis.
    Trends Biochem Sci. 1998 Oct;23(10):399-402 PMID: 9810229
  32. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.
    Science. 1998 Dec 4;282(5395):1893-7 PMID: 9836640
  33. Cell cycle. Checkpoint on the nuclear frontier.
    Nature. 1999 Jan 14;397(6715):104-5 PMID: 9923668
  34. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway.
    Oncogene. 1999 Jul 15;18(28):4047-54 PMID: 10435585
  35. Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine.
    Cancer Res. 1999 Sep 1;59(17):4375-82 PMID: 10485486
  36. Atm haploinsufficiency results in increased sensitivity to sublethal doses of ionizing radiation in mice.
    Nat Genet. 1999 Apr;21(4):359-60 PMID: 10192382
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
Published
2000-02-15
Pages
397-402
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC316378
Subset
IM
External Links
PubMed source PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2