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J. Biol. Chem., Vol. 281, Issue 28, 19038-19044, July 14, 2006

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Up-regulation of the Fidelity of Human DNA Polymerase by Its Non-enzymatic Proline-rich Domain^*

Kevin A. Fiala¹, Wade W. Duym, Jun Zhang, and Zucai Suo^¶||**2

From the Department of Biochemistry, the Biochemistry Program, the ^¶Biophysics Program, the ^||Molecular, Cellular & Developmental Biology Program, and the ^**Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210

DNA repair pathways are essential for maintaining genome stability. DNA polymerase plays a critical role in base-excision repair in vivo. DNA polymerase , a recently identified X-family homolog of DNA polymerase , is hypothesized to be a second polymerase involved in base-excision repair. The full-length DNA polymerase is comprised of three domains: a C-terminal DNA polymerase -like domain, an N-terminal BRCA1 C-terminal domain, and a previously uncharacterized proline-rich domain. Strikingly, pre-steady-state kinetic analyses reveal that, although human DNA polymerase has almost identical fidelity to human DNA polymerase , the C-terminal DNA polymerase -like domain alone displays a dramatic, up to 100-fold loss in fidelity. We further demonstrate that the non-enzymatic proline-rich domain confers the increase in fidelity of DNA polymerase by significantly lowering incorporation rate constants of incorrect nucleotides. Our studies illustrate a novel mechanism, in which the DNA polymerase fidelity is controlled not by an accessory protein or a proofreading exonuclease domain but by an internal regulatory domain.

Received for publication, February 7, 2006 , and in revised form, May 1, 2006.

^* This work was supported in part by a startup fund (to Z. S.) provided by the Ohio State University. 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 Supported by the National Institutes of Health Chemistry and Biology Interface Program at the Ohio State University (Grant T32 GM08512-08) and the American Heart Association Predoctoral Fellowship (Grant 0415129B).

² To whom correspondence should be addressed: 740 Biological Sciences, 484 West 12th Ave., Columbus, OH 43210. Tel.: 614-688-3706; Fax: 614-292-6773; E-mail: suo.3{at}osu.edu.

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