title: ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair.
abstract: 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.
authors.affiliation: Genome Stability Unit, Clare Laboratories, London Research Institute, Cancer Research UK, South Mimms, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cosentino
authors.forename: Domenico
authors.initials: D
authors.lastname: Grieco
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Costanzo
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics* / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D047468:Immunoprecipitation; D007211:Indoles; D010427:Pentose Phosphate Pathway / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014981:Xenopus
chemical_list: D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D055551:HSP27 Heat-Shock Proteins; D006657:Histones; D007211:Indoles; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; C007293:DAPI; D005954:Glucosephosphate Dehydrogenase; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases