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PNAS 106 (18): 7525-7530

Copyright © 2009 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

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

Miriam Marquésa,1, Amit Kumara,1, Ana M. Povedab, Susana Zuluagaa, Carmen Hernándeza, Shaun Jacksonc, Philippe Paserob, and Ana C. Carreraa,2

aDepartment of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid E-28049, Spain; bInstitute of Human Genetics, Centre National de la Recherche Scientifique Unité Propre de Recherche 1142, 141 Rue de la Cardonille, F-34396 Montpellier, France; and cAustralian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia

Edited by Inder M. Verma, The Salk Institute for Biological Studies, La Jolla, CA, and approved March 20, 2009

Received for publication November 25, 2008.

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, {alpha} 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 {delta}. 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.

Author contributions: A.C.C. designed research; M.M., A.K., A.M.P., S.Z., and C.H. performed research; S.J. contributed new reagents/analytic tools; M.M., A.K., P.P., and A.C.C. analyzed data; and A.C.C. wrote the paper.

1M.M. and A.K. contributed equally to this work.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0812000106/DCSupplemental.

2To whom correspondence should be addressed. E-mail: acarrera{at}cnb.csic.es

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