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Phosphorylation of cyclin D1 regulated by ATM or ATR controls cell cycle progression

Masahiro Hitomi1, Ke Yang, Andrew W Stacey

  • 1Department of Molecular Genetics, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

Molecular and Cellular Biology
|July 9, 2008
PubMed

Insights

Checkpoint kinases ATR and ATM regulate cell cycle progression by phosphorylating cyclin D1. This phosphorylation is crucial for DNA synthesis and cell cycle control in both normal and stressed cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Cyclin D1 levels must be tightly regulated for proper cell cycle progression.
  • High cyclin D1 is needed for G1 phase, but low levels are required during S phase to prevent DNA synthesis inhibition.

Purpose of the Study:

  • To investigate the role of checkpoint kinase ATR in regulating cyclin D1 phosphorylation.
  • To determine if ATR influences cyclin D1 phosphorylation in normal and DNA-damaged cells.

Main Methods:

  • Utilized UV irradiation and topoisomerase IIbeta binding protein 1 activator to induce DNA stress.
  • Employed small interfering RNA (siRNA) to inhibit ATR.
  • Assessed cyclin D1 phosphorylation at Thr286.
  • Investigated the role of ATM in response to double-stranded DNA breaks.

Main Results:

  • ATR activation by UV or specific activators promoted cyclin D1 phosphorylation.
  • ATR inhibition reduced UV-induced and basal cyclin D1 phosphorylation.
  • ATM also promoted cyclin D1 Thr286 phosphorylation following double-stranded DNA breaks.
  • Exogenous cyclin D1 expression overcame G1 cell cycle arrest induced by DNA damage.

Conclusions:

  • Checkpoint kinases, including ATR and ATM, play a critical role in regulating cell cycle progression.
  • These kinases direct cyclin D1 phosphorylation, impacting DNA synthesis and cell cycle control.
  • Cyclin D1 regulation by checkpoint kinases is essential in both normal and stressed cellular conditions.

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