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Phosphorylation of Sp1 in response to DNA damage by ataxia telangiectasia-mutated kinase

Beatrix A Olofsson1, Crystal M Kelly, Jiyoon Kim

  • 1Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.

Molecular Cancer Research : MCR
|January 4, 2008
PubMed

Insights

Sp1 is a novel ATM kinase substrate involved in DNA damage response. Phosphorylation of Sp1 by ATM is critical for cellular repair and survival following DNA damage.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • Sp1 is a transcription factor regulating essential genes.
  • Sp1 contains SQ/TQ cluster domains, characteristic of ATM kinase substrates.
  • ATM substrates are key players in the DNA damage response (DDR).

Purpose of the Study:

  • To investigate the role of Sp1 in the DNA damage response.
  • To determine if Sp1 is a substrate of ATM kinase.
  • To identify the specific ATM phosphorylation site on Sp1.

Main Methods:

  • Activation and inhibition of ATM kinase.
  • Analysis of Sp1 phosphorylation kinetics.
  • Cellular sensitivity assays to DNA damage.
  • Site-directed mutagenesis of Sp1 (S101A).

Main Results:

  • ATM activation induced Sp1 phosphorylation, similar to H2AX.
  • Inhibition of ATM blocked Sp1 phosphorylation.
  • Sp1 depletion sensitized cells to DNA damage and increased double-strand breaks.
  • Serine 101 was identified as the critical ATM phosphorylation site on Sp1.

Conclusions:

  • Sp1 is a novel substrate of ATM kinase.
  • Sp1 phosphorylation by ATM is crucial for the DNA damage response.
  • Sp1 plays a significant role in maintaining genomic stability.

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