ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background.

Journal Article (Journal Article)

The ataxia-telangiectasia mutated and rad3-related (ATR) kinase orchestrates cellular responses to DNA damage and replication stress. Complete loss of ATR function leads to chromosomal instability and cell death. However, heterozygous ATR mutations are found in human cancers with microsatellite instability, suggesting that ATR haploinsufficiency contributes to tumorigenesis. To test this possibility, we generated human cell line and mouse model systems in which a single ATR allele was inactivated on a mismatch repair (MMR)-deficient background. Monoallelic ATR gene targeting in MLH1-deficient HCT 116 colon carcinoma cells resulted in hypersensitivity to genotoxic stress accompanied by dramatic increases in fragile site instability, and chromosomal amplifications and rearrangements. The ATR(+/-) HCT 116 cells also displayed compromised activation of Chk1, an important downstream target for ATR. In complementary studies, we demonstrated that mice bearing the same Atr(+/-)/Mlh1(-/-) genotype were highly prone to both embryonic lethality and early tumor development. These results demonstrate that MMR proteins and ATR functionally interact during the cellular response to genotoxic stress, and that ATR serves as a haploinsufficient tumor suppressor in MMR-deficient cells.

Full Text

Duke Authors

Cited Authors

  • Fang, Y; Tsao, C-C; Goodman, BK; Furumai, R; Tirado, CA; Abraham, RT; Wang, X-F

Published Date

  • August 4, 2004

Published In

Volume / Issue

  • 23 / 15

Start / End Page

  • 3164 - 3174

PubMed ID

  • 15282542

Pubmed Central ID

  • PMC514932

International Standard Serial Number (ISSN)

  • 0261-4189

Digital Object Identifier (DOI)

  • 10.1038/sj.emboj.7600315


  • eng

Conference Location

  • England