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Nucleic Acids Research 2005 33(8):2715-2725; doi:10.1093/nar/gki569
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Published online 11 May 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

Regulation of ribonucleotide reductase M2 expression by the upstream AUGs

Zizheng Dong, Yang Liu and Jian-Ting Zhang*

Department of Pharmacology and Toxicology, Indiana University Cancer Center, Walther Oncology Center, Walther Cancer Institute, Indiana University School of Medicine 1044 W. Walnut Street, R4-166, Indianapolis, IN 46202, USA

*To whom correspondence should be addressed. Tel: +1 317 278 4503; Fax: +1 317 274 8046; Email: jianzhan{at}iupui.edu

Received January 3, 2005. Revised April 21, 2005. Accepted April 21, 2005.

Ribonucleotide reductase catalyzes a rate-limiting reaction in DNA synthesis by converting ribonucleotides to deoxyribonucleotides. It consists of two subunits and the small one, M2 (or R2), plays an essential role in regulating the enzyme activity and its expression is finely controlled. Changes in the M2 level influence the dNTP pool and, thus, DNA synthesis and cell proliferation. M2 gene has two promoters which produce two major mRNAs with 5'-untranslated regions (5'-UTRs) of different lengths. In this study, we found that the M2 mRNAs with the short (63 nt) 5'-UTR can be translated with high efficiency whereas the mRNAs with the long (222 nt) one cannot. Examination of the long 5'-UTR revealed four upstream AUGs, which are in the same reading frame as the unique physiological translation initiation codon. Further analysis demonstrated that these upstream AUGs act as negative cis elements for initiation at the downstream translation initiation codon and their inhibitory effect on M2 translation is eIF4G dependent. Based on the findings of this study, we conclude that the expression of M2 is likely regulated by fine tuning the translation from the mRNA with a long 5'-UTR during viral infection and during the DNA replication phase of cell proliferation.


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