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

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, alpha has selective action in cell growth and cell cycle entry, but no specific function in cell division has been described for beta. We report here a unique function for PI3K beta in the control of DNA replication. PI3K beta regulated DNA replication through kinase-dependent and kinase-independent mechanisms. PI3K beta was found in the nucleus, where it associated PKB. Modulation of PI3K beta activity altered the DNA replication rate by controlling proliferating cell nuclear antigen (PCNA) binding to chromatin and to DNA polymerase delta. PI3K beta exerted this action by regulating the nuclear activation of PKB in S phase, and in turn phosphorylation of PCNA negative regulator p21(Cip). Also, p110 beta associated with PCNA and controlled PCNA loading onto chromatin in a kinase-independent manner. These results show a selective function of PI3K beta in the control of DNA replication.