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J. Biol. Chem., Vol. 278, Issue 38, 36403-36409, September 19, 2003

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Characterization of Novel Reverse Transcriptase and Other RNA-associated Catalytic Activities by Human DNA Polymerase

IMPORTANCE IN MITOCHONDRIAL DNA REPLICATION^*

Eisuke Murakami , Joy Y. Feng , Harold Lee , Jeremiah Hanes , Kenneth A. Johnson  and Karen S. Anderson  ¶

From the Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8066 and the Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas 78712

During mitochondrial DNA (mtDNA) replication, DNA/RNA heteroduplex intermediates are formed. To understand how and why ribonucleotides are involved in mtDNA replication, we have studied the novel RNA-associated activities of human mitochondrial DNA polymerase (Pol ), including reverse transcription, RNA-directed 3' 5' DNA excision, RNA-primed DNA synthesis, and ribonucleotide incorporation. Remarkably, Pol catalyzes reverse transcription with a slightly higher efficiency than HIV-1 reverse transcriptase, suggesting that the activity may be physiologically significant, and furthermore, proofreading activity with an RNA template was also observed. RNA-primed DNA synthesis activity is required for initiation of mtDNA replication, and we have found that Pol holoenzyme is capable of performing this reaction at a physiologically relevant rate and that the accessory subunit plays an essential role in the initiation steps. Single ribonucleotides have been found scattered in the mtDNA genome, although their role and significance are not yet defined. Our finding that Pol also incorporates ribonucleotide triphosphates into a DNA primer offers a plausible enzymatic pathway for the origin of the RNA-containing mtDNA genome.

Received for publication, June 9, 2003

^* This work was supported by National Institutes of Health Grants GM 49551 (to K. S. A.) and GM 044613 (to K. A. J.). 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: Dept. of Pharmacology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520-8066. Tel.: 203-785-4526; Fax: 203-785-7670; E-mail: karen.anderson{at}yale.edu.

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