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Originally published In Press as doi:10.1074/jbc.M009599200 on February 8, 2001

J. Biol. Chem., Vol. 276, Issue 21, 18235-18242, May 25, 2001
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Replication Protein A as a "Fidelity Clamp" for DNA Polymerase alpha *

Giovanni MagaDagger §, Isabelle FrouinDagger , Silvio SpadariDagger , and Ulrich Hübscher||

From the Dagger  Istituto di Genetica Biochimica ed Evoluzionistica-Consiglio Nazionale delle Ricerche, I-27100 Pavia, Italy and the || Institut für Veterinärbiochemie, Universität Zürich-Irchel, 8057 Zürich, Switzerland

The current view of DNA replication in eukaryotes predicts that DNA polymerase alpha  (pol alpha )-primase synthesizes the first 10-ribonucleotide-long RNA primer on the leading strand and at the beginning of each Okazaki fragment on the lagging strand. Subsequently, pol alpha  elongates such an RNA primer by incorporating about 20 deoxynucleotides. pol alpha  displays a low processivity and, because of the lack of an intrinsic or associated 3'right-arrow 5' exonuclease activity, it is more error-prone than other replicative pols. Synthesis of the RNA/DNA primer catalyzed by pol alpha -primase is a critical step in the initiation of DNA synthesis, but little is known about the role of the DNA replication accessory proteins in its regulation. In this paper we provide evidences that the single-stranded DNA-binding protein, replication protein A (RP-A), acts as an auxiliary factor for pol alpha  playing a dual role: (i) it stabilizes the pol alpha /primer complex, thus acting as a pol clamp; and (ii) it significantly reduces the misincorporation efficiency by pol alpha . Based on these results, we propose a hypothetical model in which RP-A is involved in the regulation of the early events of DNA synthesis by acting as a "fidelity clamp" for pol alpha .

* This work was supported by grants from the European Union-Training and Mobility of Human Resources program (EU-TMR) (ERBMRXCT 970125 to S. S. and U. H.), the Consiglio Nazionale delle Ricerche Target Project on Biotechnology (to S. S.), and the Kanton of Zürich (to U. H. and G. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a fellowship from the EU-TMR Network (Grant ERBMRXCT 970125).

§ To whom correspondence should be addressed: IGBE-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy. Tel.: 39-0382546355; Fax: 39-0382422286; E-mail: maga@igbe.pv.cnr.it.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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