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J. Biol. Chem., Vol. 278, Issue 29, 26750-26756, July 18, 2003

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Protein Kinase A-anchoring Protein AKAP95 Interacts with MCM2, a Regulator of DNA Replication^*

Turid Eide  , Kristin A. Taskén  , Cathrine Carlson , Gareth Williams ¶, Tore Jahnsen , Kjetil Taskén  || and Philippe Collas 

From the Department of Medical Biochemistry, University of Oslo, P. O. Box 1112 Blindern, 0317 Oslo, Norway and ^¶Department of Pathology, Division of Molecular and Cellular Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom

Protein kinase A (PKA)-anchoring protein AKAP95 is localized to the nucleus in interphase, where it primarily associates with the nuclear matrix. A yeast two-hybrid screen for AKAP95 interaction partners identified the minichromosome maintenance (MCM) 2 protein, a component of the pre-replication complex. AKAP95-MCM2 interaction was mapped to residues 1–195 of AKAP95 and corroborated by glutathione S-transferase precipitation and immunoprecipitation from chromatin. Disruption of AKAP95-MCM2 interaction with an AKAP95-(1–195) peptide within HeLa cell nuclei abolishes initiation of DNA replication in G₁ phase and the elongation phase of replication in vitro without affecting global nuclear organization or import. Disruption of the C-terminal zinc finger of AKAP95 reduces efficiency of replication initiation. Disruption of the PKA-binding domain does not impair replication in G₁- or S-phase nuclei, whereas a PKA inhibitor affects the initiation but not the elongation phase of replication. Depleting AKAP95 from nuclei partially depletes MCM2 and abolishes replication. Recombinant AKAP95 restores intranuclear MCM2 and replication in a dose-dependent manner. Our results suggest a role of AKAP95 in DNA replication by providing a scaffold for MCM2.

Received for publication, January 23, 2003 , and in revised form, April 9, 2003.

^* This work was supported by grants from the Norwegian Cancer Society, the Norwegian Research Council, the Foundation for Health and Rehabilitation, Novo Nordisk, the Anders Jahre Foundation, and the Human Frontiers Science Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Dept. of Medical Biochemistry, University of Oslo, P. O. Box 1112 Blindern, N-0317 Oslo, Norway. Tel.: 47-22851454; Fax: 47-22851497; E-mail: kjetil.tasken{at}basalmed.uio.no.

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