Comparative phosphoproteomic analysis of checkpoint recovery identifies new regulators of the DNA damage response

Vincentius A Halim1, Mónica Alvarez-Fernández, Yan Juan Xu

  • 1Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands.

Science Signaling
|April 25, 2013
PubMed

Insights

Researchers identified how cells recover from DNA damage-induced cell cycle arrest. Astrin protein controls p53 levels, enabling cells to resume cell cycle progression after DNA damage.

Area of Science:

  • Cell biology
  • Molecular biology
  • Genetics

Background:

  • Cell cycle arrest is a crucial response to DNA damage.
  • Mechanisms governing cell cycle recovery remain poorly understood.

Purpose of the Study:

  • To identify key proteins and pathways involved in cell cycle recovery after DNA damage.
  • To elucidate the role of specific proteins in regulating cell cycle progression during DNA damage response.

Main Methods:

  • Large-scale quantitative phosphoproteomics to identify differentially phosphorylated proteins.
  • Systematic depletion of identified proteins using small interfering RNA (siRNA) to assess their function.
  • Analysis of protein abundance (p53, MDM2) and gene expression during recovery.

Main Results:

  • Identified 154 differentially phosphorylated proteins during recovery from G2 arrest.
  • Astrin, a mitotic spindle-associated protein, was identified as a potential regulator of recovery.
  • Astrin depletion led to decreased MDM2 and increased p53 levels, impacting DNA damage response.
  • Astrin is required for maintaining gene expression that promotes cell cycle progression.

Conclusions:

  • Astrin plays a critical role in cell cycle recovery by controlling p53 abundance.
  • Astrin ensures cells remain competent to resume the cell cycle after DNA damage.
  • This study reveals a novel mechanism for regulating cell cycle progression following DNA damage.

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