Nuclear phosphoinositide 3-kinase β controls double-strand break DNA repair

Abstract

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 β (PI3Kβ) isoform, but not its activity, is essential for early embryonic development. Nonetheless, the specific function of PI3Kβ 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 PI3Kβ is necessary for DSB sensing, as PI3Kβ regulates binding of the Nbs1 sensor protein to damaged DNA. Indeed, Nbs1 did not bind to DSB in PI3Kβ-deficient cells, which showed a general defect in subsequent ATM and ATR activation, resulting in genomic instability. Inhibition of PI3Kβ also retarded the DNA repair but the defect was less marked than that induced by PI3Kβ deletion, supporting a kinase-independent function for PI3Kβ in DNA repair. These results point at class I PI3Kβ as a critical sensor of genomic integrity.

MRE11 promotes AKT phosphorylation in direct response to DNA double-strand breaks

“…27 However, LY294002 also inhibits DNA-PKcs at concentrations similar to those that inhibit PI3K and LY294002-induced radiosensitivity correlates with inhibition of DNA-PKcs, 53 making interpretation of these data difficult. In contrast, our data suggest that DSB-induced pAKT-S473 accumulation is PI3K-independent, which may have important ramifications for the potential utility of novel radiosensitizing agents that target AKT via the ablation of PI3K-dependent signaling, since our model predicts that these agents may not affect the DSB-induced, PI3K-independent phosphorylation of pAKT-S473.…”

“…The canonical mechanism of AKT phosphorylation involves PI3K, which is present in the nucleus and accumulates at DSB, 27 although PI3K-independent mechanisms have been described. [28][29][30] To assess whether PI3K is required for the MRE11-dependent accumulation of pAKT-S473, we utilized the PI3K inhibitor LY294002, which blocks both endogenous and seruminduced pAKT-S473 in normal fibroblasts (Sup.…”

The Promise of Combining Inhibition of PI3K and PARP as Cancer Therapy

“…Activation of the PI3K pathway is a common feature of many tumor types and leads to the stimulation of cell growth, mobility, survival, and metabolism ( 7 ), and also sensing of DSBs during DNA repair ( 8 ).…”

Rationale-based therapeutic combinations with PI3K inhibitors in cancer treatment

“…161 However, in addition to the role of p110a in the DNA damage response, activation of p110b by DNA damage seems to play a critical role in recognition of DNA double-strand breaks and recruitment of NBS1 to sites of DNA damage. 162 Loss of p110b leads to impaired recruitment of downstream DNA damage repair mediators such as ATM, RAD17, g-H2AX, and 53BP. 162 In contrast to AKT, several reports have shown that mTORC1 signaling is actually downregulated as a result of DNA damage.…”

“…162 Loss of p110b leads to impaired recruitment of downstream DNA damage repair mediators such as ATM, RAD17, g-H2AX, and 53BP. 162 In contrast to AKT, several reports have shown that mTORC1 signaling is actually downregulated as a result of DNA damage. [163][164][165] Oxidative stress was shown to downregulate mTORC1 signaling by activating ATM, leading to a phosphorylation chain resulting in sequential activation of LKB1, AMPK, and finally TSC2.…”