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Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis

E Y So1, M Ausman, T Saeki

  • 1Department of Medicine, NUHS, Systems Biology Program, Pritzker School of Medicine, The University of Chicago, Evanston, IL 60201, USA.

Cell Death & Disease
|March 11, 2011
PubMed

Insights

Hypoxia-induced DNA damage activates the ATR-SMC1 pathway, leading to apoptosis. This study reveals how desferrioxamine triggers this response via Structural Maintenance of Chromosomes 1 (SMC1) phosphorylation, impacting DNA damage checkpoints.

Area of Science:

  • Cellular biology
  • Molecular oncology
  • DNA damage response

Background:

  • DNA damage signaling pathways are crucial for cellular integrity, responding to various stressors including hypoxia.
  • Structural Maintenance of Chromosomes 1 (SMC1) is recognized for its role in the cohesion complex and its involvement in DNA damage checkpoint activation.

Purpose of the Study:

  • To elucidate the mechanism of the DNA damage checkpoint activated by the ATR-SMC1 pathway under hypoxia-mimetic conditions.
  • To investigate the role of SMC1 phosphorylation in desferrioxamine (DFO)-induced cellular responses.

Main Methods:

  • Treatment of cells with desferrioxamine (DFO) to mimic hypoxia.
  • Analysis of protein phosphorylation at specific sites (SMC1 Ser966, NBS1 Ser343, Chk1 Ser317, Chk2 Thr68, p53 Ser15).
  • Utilizing ATR-deficient and ATM/DNA-PKcs-deficient cells to determine kinase involvement.
  • Assessing apoptosis and HIF1α levels.
  • Employing site-directed mutagenesis (SMC1 S966A).

Main Results:

  • DFO treatment induced phosphorylation of SMC1, NBS1, Chk1, Chk2, and p53.
  • ATR mediated the DFO-induced phosphorylation of SMC1, NBS1, and Chk1, as evidenced by reduced phosphorylation in ATR-deficient cells.
  • DFO-induced apoptosis was diminished in ATR-mutant cells, despite normal p53 activation.
  • Expression of SMC1 S966A mutant attenuated DFO-induced apoptosis and Chk1 phosphorylation.

Conclusions:

  • The ATR-SMC1 pathway is a key mediator of DFO-induced apoptosis under hypoxia-mimetic conditions.
  • Phosphorylation of SMC1 at Ser966 by ATR is critical for activating downstream signaling, including Chk1 phosphorylation and subsequent apoptosis.
  • The findings highlight a specific mechanism by which hypoxia influences DNA damage signaling and cell fate.

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