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EMBO J 2011 Feb 02;303:546-55. doi: 10.1038/emboj.2010.330.
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ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair.

Cosentino C , Grieco D , Costanzo V .

Ataxia telangiectasia (A-T) is a human disease caused by ATM deficiency characterized among other symptoms by radiosensitivity, cancer, sterility, immunodeficiency and neurological defects. ATM controls several aspects of cell cycle and promotes repair of double strand breaks (DSBs). This probably accounts for most of A-T clinical manifestations. However, an impaired response to reactive oxygen species (ROS) might also contribute to A-T pathogenesis. Here, we show that ATM promotes an anti-oxidant response by regulating the pentose phosphate pathway (PPP). ATM activation induces glucose-6-phosphate dehydrogenase (G6PD) activity, the limiting enzyme of the PPP responsible for the production of NADPH, an essential anti-oxidant cofactor. ATM promotes Hsp27 phosphorylation and binding to G6PD, stimulating its activity. We also show that ATM-dependent PPP stimulation increases nucleotide production and that G6PD-deficient cells are impaired for DSB repair. These data suggest that ATM protects cells from ROS accumulation by stimulating NADPH production and promoting the synthesis of nucleotides required for the repair of DSBs.

PubMed ID: 21157431
PMC ID: PMC3034007
Article link: EMBO J
Grant support: [+]

Species referenced: Xenopus
Genes referenced: atm bcr g6pd hspb1 tigar tp53 ubl4a
GO keywords: glucose-6-phosphate dehydrogenase activity [+]

Disease Ontology terms: ataxia telangiectasia

Article Images: [+] show captions
References [+] :
Ayene, Oxidation of cellular thiols by hydroxyethyldisulphide inhibits DNA double-strand-break rejoining in G6PD deficient mammalian cells. 2000, Pubmed