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J. Biol. Chem., Vol. 283, Issue 27, 19095-19111, July 4, 2008

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Cellular Functions of Human RPA1

MULTIPLE ROLES OF DOMAINS IN REPLICATION, REPAIR, AND CHECKPOINTS^*

From the Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242

In eukaryotes, the single strand DNA (ssDNA)-binding protein, replication protein A (RPA), is essential for DNA replication, repair, and recombination. RPA is composed of the following three subunits: RPA1, RPA2, and RPA3. The RPA1 subunit contains four structurally related domains and is responsible for high affinity ssDNA binding. This study uses a depletion/replacement strategy in human cells to reveal the contributions of each domain to RPA cellular functions. Mutations that substantially decrease ssDNA binding activity do not necessarily disrupt cellular RPA function. Conversely, mutations that only slightly affect ssDNA binding can dramatically affect cellular function. The N terminus of RPA1 is not necessary for DNA replication in the cell; however, this region is important for the cellular response to DNA damage. Highly conserved aromatic residues in the high affinity ssDNA-binding domains are essential for DNA repair and cell cycle progression. Our findings suggest that as long as a threshold of RPA-ssDNA binding activity is met, DNA replication can occur and that an RPA activity separate from ssDNA binding is essential for function in DNA repair.

Received for publication, February 1, 2008 , and in revised form, May 5, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant GM44721 (to M. S. W.). This work was also supported by American Heart Association Postdoctoral Fellowship 0525735Z (to S. J. H.). 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.

¹ Present address: Dept. of Biochemistry and Molecular Biophysics, Washington University, St. Louis, MO 63110.

² To whom correspondence should be addressed: University of Iowa, Carver College of Medicine, Dept. of Biochemistry, 3107 MERF, Iowa City, IA 52242. Tel.: 319-335-6784; Fax: 319-384-4770; E-mail: marc-wold{at}uiowa.edu.

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