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

Yanan Fang1, Cheng-Chung Tsao, Barbara K Goodman

  • 1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.

The EMBO Journal
|July 30, 2004
PubMed

Insights

Ataxia-telangiectasia mutated and rad3-related (ATR) haploinsufficiency in mismatch repair-deficient cells causes genomic instability and cancer. This highlights ATR

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • The ataxia-telangiectasia mutated and rad3-related (ATR) kinase is crucial for DNA damage and replication stress response.
  • Complete ATR loss causes cell death, but heterozygous mutations are linked to microsatellite unstable cancers.
  • ATR haploinsufficiency's role in tumorigenesis, particularly in mismatch repair (MMR)-deficient contexts, remains to be fully elucidated.

Purpose of the Study:

  • To investigate the functional consequences of ATR haploinsufficiency in MMR-deficient cells.
  • To determine if ATR haploinsufficiency contributes to tumorigenesis in a genetically engineered model.

Main Methods:

  • Generated human cell lines (HCT 116) and mouse models with monoallelic ATR inactivation on an MMR-deficient background (MLH1-/-).
  • Assessed cellular responses to genotoxic stress, including Chk1 activation, fragile site instability, and chromosomal aberrations.
  • Evaluated embryonic lethality and tumor development in mice with the Atr(+/-)/Mlh1(-/-) genotype.

Main Results:

  • Monoallelic ATR inactivation in MLH1-deficient cells led to hypersensitivity to genotoxic stress, increased chromosomal instability, and impaired Chk1 activation.
  • Atr(+/-)/Mlh1(-/-) mice exhibited high rates of embryonic lethality and early tumor development.
  • These findings demonstrate a functional interaction between MMR proteins and ATR.

Conclusions:

  • ATR acts as a haploinsufficient tumor suppressor in MMR-deficient cells.
  • The study reveals a critical role for ATR in maintaining genomic stability within the context of MMR deficiency.
  • MMR proteins and ATR functionally cooperate in cellular responses to genotoxic stress, impacting cancer development.

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