Hypoxic activation of ATR and the suppression of the initiation of DNA replication through cdc6 degradation

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L Martin1, M Rainey, C Santocanale

  • 1Department of Medicine, NYU School of Medicine, New York, NY, USA.

Oncogene
|December 20, 2011
PubMed

Insights

Hypoxia inhibits DNA replication initiation via ATR kinase activating a checkpoint. This leads to cdc6 degradation, preventing cell replication in hypoxic tumors.

Area of Science:

  • Cell biology
  • Molecular oncology
  • DNA replication

Background:

  • Severely hypoxic cells often fail to initiate DNA replication, a mechanism not fully understood.
  • The ataxia-telangiectasia-rad3 related (ATR) kinase is activated by hypoxia, but its downstream effects on DNA replication are unclear.

Purpose of the Study:

  • To elucidate the mechanism by which hypoxia inhibits DNA replication initiation.
  • To define the role of ATR kinase in the DNA replication initiation checkpoint under hypoxic conditions.

Main Methods:

  • Investigated the DNA replication initiation checkpoint in hypoxic cells.
  • Assessed the role of ATR kinase in regulating cdc25a phosphatase, CDK2 activity, and cdc6 degradation.
  • Utilized ATR depletion to observe effects on DNA replication initiation.

Main Results:

  • ATR activation in hypoxic cells triggers phosphorylation-dependent degradation of cdc25a phosphatase.
  • ATR-mediated cdc25a downregulation reduces CDK2 activity, leading to cdc6 degradation by APC/C(Cdh1).
  • ATR depletion in hypoxic cells maintains DNA replication initiation.

Conclusions:

  • ATR plays a central role in inhibiting DNA replication initiation under hypoxia by regulating cdc6 degradation via APC/C(Cdh1).
  • This mechanism provides insights into hypoxic tumor biology and potential therapeutic strategies.

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