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J. Biol. Chem., Vol. 278, Issue 22, 19649-19659, May 30, 2003

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Identification of a cis-Element That Determines Autonomous DNA Replication in Eukaryotic Cells^*

Gerald B. Price  , Minna Allarakhia  ¶, Nandini Cossons ||, Torsten Nielsen ** , Maria Diaz-Perez , Paula Friedlander , Liang Tao  and Maria Zannis-Hadjopoulos 

From the McGill Cancer Centre, McGill University, Montreal, Quebec H3G 1Y6, the ^||Department of Internal Medicine, the Ottawa Hospital-General Campus, Ottawa, Ontario K1H 8L6, and the ^**Faculty of Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

A 36-bp human consensus sequence (CCTMDAWKSGBYTSMAAWTWBCMYTTRSCAAATTCC) is capable of supporting autonomous replication of a plasmid after transfection into eukaryotic cells. After transfection and in vitro DNA replication, replicated plasmid DNA containing a mixture of oligonucleotides of this consensus was found to reiterate the consensus. Initiation of DNA replication in vitro occurs within the consensus. One version, A3/4, in pYACneo, could be maintained under selection in HeLa cells, unrearranged and replicating continuously for >170 cell doublings. Stability of plasmid without selection was high (≥0.9/cell/generation). Homologs of the consensus are found consistently at mammalian chromosomal sites of initiation and within CpG islands. Versions of the consensus function as origins of DNA replication in normal and malignant human cells, immortalized monkey and mouse cells, and normal cow, chicken, and fruit fly cells. Random mutagenesis studies suggest an internal 20-bp consensus sequence of the 36 bp may be sufficient to act as a core origin element. This cis-element consensus sequence is an opportunity for focused analyses of core origin elements and the regulation of initiation of DNA replication.

Received for publication, July 12, 2002 , and in revised form, March 12, 2003.

^* This work was supported in part by grants from the Cancer Research Society (to G. B. P.), the Canadian Institutes of Health Research (to M. Z.-H.), and REPLICor, Inc. 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.

^¶ Recipient of an Fonds pour la Formation de Chercheurs et l'Aide à Recherche Centre Studentship and Canadian Institutes of Health Research doctoral research studentship.

Recipient of a Canadian Institutes of Health Research studentship.

To whom correspondence should be addressed: McGill Cancer Centre, McGill University, 3655 Sir William Osler Promenade, Montreal, Quebec H3G 1Y6, Canada.

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