Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 16, Pages 7491-7496Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0914242107
Keywords
cancer; genomic integrity
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Funding
- Spanish Association Against Cancer
- Spanish Ministry of Science and Innovation [SAF2004-05955, RD07/0020/2020]
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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 (PI3K beta) isoform, but not its activity, is essential for early embryonic development. Nonetheless, the specific function of PI3K beta 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 PI3K beta is necessary for DSB sensing, as PI3K beta regulates binding of the Nbs1 sensor protein to damaged DNA. Indeed, Nbs1 did not bind to DSB in PI3K beta-deficient cells, which showed a general defect in subsequent ATM and ATR activation, resulting in genomic instability. Inhibition of PI3K beta also retarded the DNA repair but the defect was less marked than that induced by PI3K beta deletion, supporting a kinase-independent function for PI3K beta in DNA repair. These results point at class I PI3K beta as a critical sensor of genomic integrity.
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