2005. Regulation of ribonucleotide reductase M2 expression by the upstream AUGs. Nucleic Acids Res

Ribonucleotide reductase catalyzes a rate-limiting reaction in DNA synthesis by converting ribonucleo-tides to deoxyribonucleotides. It consists of two sub-units and the small one, M2 (or R2), plays an essential role in regulating the enzyme activity and its expres-sion is finely controlled. Changes in the M2 level influ-ence the dNTP pool and, thus, DNA synthesis and cell proliferation. M2 gene has two promoters which pro-duce two major mRNAs with 50-untranslated regions (50-UTRs) of different lengths. In this study, we found that the M2 mRNAs with the short (63 nt) 50-UTR can be translated with high efficiency whereas the mRNAs with the long (222 nt) one cannot. Examination of the long50-UTRrevealedfourupstream AUGs,whicharein the same reading frame as the unique physiological translation initiation codon. Further analysis demon-strated that these upstream AUGs act as negative cis elements for initiation at the downstream translation initiationcodon and their inhibitoryeffect onM2trans-lation 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 50-UTR during viral infection and during the DNA replication phase of cell proliferation