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J. Biol. Chem., Vol. 280, Issue 15, 15212-15218, April 15, 2005

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The Human TREX2 3' 5'-Exonuclease Structure Suggests a Mechanism for Efficient Nonprocessive DNA Catalysis^*

Fred W. Perrino, Scott Harvey, Sara McMillin, and Thomas Hollis

From the Department of Biochemistry, Center for Structural Biology, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157

The 3' 5'-exonucleases process DNA ends in many DNA repair pathways of human cells. Determination of the human TREX2 structure is the first of a dimeric 3'-deoxyribonuclease and indicates how this highly efficient nonprocessive enzyme removes nucleotides at DNA 3' termini. Symmetry in the TREX2 dimer positions the active sites at opposite outer edges providing open access for the DNA. Adjacent to each active site is a flexible region containing three arginines positioned appropriately to bind DNA and to control its entry into the active site. Mutation of these three arginines to alanines reduces the DNA binding capacity by 100-fold with no effect on catalysis. The human TREX2 catalytic residues overlay with the bacterial DnaQ family of 3'-exonucleases confirming the structural conservation of the catalytic sites despite limited sequence identity, and mutations of these residues decrease the still measurable activity by 10⁵-fold, confirming their catalytic role.

Received for publication, January 4, 2005

The atomic coordinates and structure factors (code 1Y97) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Grant RO1 GM069962 (to F. P.) and American Cancer Society Grant RSG-04-187-01-GMC (to T. 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.

To whom correspondence should be addressed. Tel.: 336-716-0768; Fax: 336-777-3242; E-mail: thollis{at}wfubmc.edu.

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