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Role of DNA damage response pathways in preventing carcinogenesis caused by intrinsic replication stress

M D Wallace1, T L Southard2, K J Schimenti3

  • 11] Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA [2] Department of Molecular Biology and Genetics, Ithaca, NY, USA.

Oncogene
|August 27, 2013
PubMed

Insights

Defective DNA replication causes genomic instability and cancer. The ataxia telangiectasia-mutated (ATM) pathway is crucial for suppressing cancer and ensuring survival in mice with replication defects.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Defective DNA replication is linked to genomic instability, cancer, and developmental issues.
  • The Mcm4(Chaos3/Chaos3) mouse model exhibits fewer dormant replication origins and more stalled forks, leading to instability and cancer.

Purpose of the Study:

  • To investigate the role of DNA damage response (DDR) genes in carcinogenesis within a model of defective DNA replication.
  • To assess the impact of ATM pathway components on cancer development and viability in Mcm4(Chaos3/Chaos3) mice.

Main Methods:

  • Utilized the Mcm4(Chaos3/Chaos3) mouse model with defects in the MCM2-7 DNA replicative helicase.
  • Generated double mutants combining Chaos3 with components of the ATM pathway (Atm, p21/Cdkn1a, Chk2/Chek2) and the ATR pathway (Hus1).
  • Analyzed tumor latency, susceptibility, embryonic fibroblast proliferation, and pathway signaling.

Main Results:

  • Mice with combined Chaos3 and ATM pathway mutations (Atm, p21/Cdkn1a, Chk2/Chek2) showed decreased tumor latency and/or increased susceptibility.
  • Female mice exhibited greater cancer susceptibility to Atm and p21 deficiency than males.
  • Atm deficiency was semilethal and impaired proliferation, suggesting ATM inhibitors could treat replication-defect tumors.
  • Hus1 deficiency did not alter tumor development or ATR signaling.

Conclusions:

  • The ATM pathway plays a critical role in cancer suppression and developmental viability under systemic replication stress.
  • ATM pathway components are essential for managing genomic instability arising from defective DNA replication.
  • ATM drug inhibitors may represent a therapeutic strategy for cancers with underlying DNA replication defects.

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