Regulation of ribonucleotide reductase M2 expression by the upstream AUGs.
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.
Dong
Zizheng
Z
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.
Liu
Yang
Y
Zhang
Jian-Ting
JT
D020121:5' Untranslated Regions; D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D018387:Codon, Initiator; D003546:Cysteine Endopeptidases / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D008969:Molecular Sequence Data; D010442:Peptide Chain Initiation, Translational; D012262:Ribonucleoside Diphosphate Reductase / Q000096:biosynthesis / Q000235:genetics*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014764:Viral Proteins / Q000378:metabolism
D020121:5' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; D018387:Codon, Initiator; D039603:Eukaryotic Initiation Factor-4G; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D003546:Cysteine Endopeptidases; C057400:picornain 2A, Picornavirus