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ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair

Claudia Cosentino1, Domenico Grieco, Vincenzo Costanzo

  • 1Genome Stability Unit, Clare Laboratories, London Research Institute, Cancer Research UK, South Mimms, UK.

The EMBO Journal
|December 16, 2010
PubMed

Insights

Ataxia telangiectasia (A-T) involves ATM deficiency. ATM regulates the pentose phosphate pathway (PPP) to produce NADPH, an antioxidant, and nucleotides, crucial for repairing DNA double-strand breaks (DSBs).

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Ataxia telangiectasia (A-T) is a human disease linked to ATM deficiency, causing radiosensitivity, cancer, immunodeficiency, and neurological issues.
  • ATM plays a key role in cell cycle control and DNA double-strand break (DSB) repair.
  • An impaired response to reactive oxygen species (ROS) may also contribute to A-T pathogenesis.

Purpose of the Study:

  • To investigate the role of ATM in the antioxidant response.
  • To elucidate the mechanism by which ATM regulates the pentose phosphate pathway (PPP).

Main Methods:

  • Investigated ATM's effect on the PPP.
  • Assessed glucose-6-phosphate dehydrogenase (G6PD) activity and NADPH production.
  • Examined Hsp27 phosphorylation and binding to G6PD.
  • Evaluated nucleotide production and DSB repair in G6PD-deficient cells.

Main Results:

  • ATM activation stimulates the PPP by increasing G6PD activity, the rate-limiting enzyme for NADPH production.
  • ATM promotes G6PD activity through Hsp27 phosphorylation and binding.
  • ATM-dependent PPP stimulation enhances nucleotide synthesis.
  • G6PD-deficient cells exhibit impaired DSB repair.

Conclusions:

  • ATM promotes an antioxidant response by stimulating NADPH production via the PPP.
  • ATM supports DNA repair by ensuring nucleotide synthesis.
  • These findings highlight a novel role for ATM in cellular defense against ROS and DNA damage.

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