Specific function of phosphoinositide 3-kinase beta in the control of DNA replication

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Abstract
Class IA phosphoinositide 3-kinase (PI3K) are enzymes comprised of a p85 regulatory and a p110 catalytic subunit that induce formation of 3-polyphosphoinositides, which activate numerous downstream targets. PI3K controls cell division. Of the 2 ubiquitous PI3K isoforms, α has selective action in cell growth and cell cycle entry, but no specific function in cell division has been described for β. We report here a unique function for PI3Kβ in the control of DNA replication. PI3Kβ regulated DNA replication through kinase-dependent and kinase-independent mechanisms. PI3Kβ was found in the nucleus, where it associated PKB. Modulation of PI3Kβ activity altered the DNA replication rate by controlling proliferating cell nuclear antigen (PCNA) binding to chromatin and to DNA polymerase δ. PI3Kβ exerted this action by regulating the nuclear activation of PKB in S phase, and in turn phosphorylation of PCNA negative regulator p21Cip. Also, p110β associated with PCNA and controlled PCNA loading onto chromatin in a kinase-independent manner. These results show a selective function of PI3Kβ in the control of DNA replication.