Nuclear phosphoinositide 3-kinase beta controls double-strand break DNA repair.
Class I phosphoinositide 3-kinases are enzymes that generate 3-poly-phosphoinositides at the cell membrane following transmembrane receptor stimulation. Expression of the phosphoinositide 3-kinase beta (PI3Kbeta) isoform, but not its activity, is essential for early embryonic development. Nonetheless, the specific function of PI3Kbeta in the cell remains elusive. Double-strand breaks (DSB) are among the most deleterious lesions for genomic integrity; their repair is required for development. We show that PI3Kbeta is necessary for DSB sensing, as PI3Kbeta regulates binding of the Nbs1 sensor protein to damaged DNA. Indeed, Nbs1 did not bind to DSB in PI3Kbeta-deficient cells, which showed a general defect in subsequent ATM and ATR activation, resulting in genomic instability. Inhibition of PI3Kbeta also retarded the DNA repair but the defect was less marked than that induced by PI3Kbeta deletion, supporting a kinase-independent function for PI3Kbeta in DNA repair. These results point at class I PI3Kbeta as a critical sensor of genomic integrity.
Kumar
Amit
A
Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Madrid E-28049, Spain.
Fernandez-Capetillo
Oscar
O
Fernadez-Capetillo
Oscar
O
Carrera
Ana C
AC
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D058534:Class I Phosphatidylinositol 3-Kinases; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D042822:Genomic Instability; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms
D018797:Cell Cycle Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; C466108:Nijmegen breakage syndrome 1 protein, mouse; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse