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A Novel Human tRNA-Dihydrouridine Synthase Involved in Pulmonary Carcinogenesis

¹ Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan and Departments of ² Surgical Oncology and ³ Surgical Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

Requests for reprints: Yusuke Nakamura, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ward, Tokyo 108-8639, Japan. Phone: 81-3-5449-5372; Fax: 81-3-5449-5433; E-mail: yusuke{at}ims.u-tokyo.ac.jp.

An increased level of dihydrouridine in tRNA^Phe was found in human malignant tissues nearly three decades ago, but its biological significance in carcinogenesis has remained unclear. Through analysis of genome-wide gene-expression profiles among non–small cell lung carcinomas (NSCLC), we identified overexpression of a novel human gene, termed hDUS2, encoding a protein that shared structural features with tRNA-dihydrouridine synthases (DUS). The deduced 493-amino-acid sequence showed 39% homology to the dihydrouridine synthase 2 enzyme (Dus2) of Saccharomycescerevisiae and contained a conserved double-strand RNA-binding motif (DSRM). We found that hDUS2 protein had tRNA-DUS activity and that it physically interacted with EPRS, a glutamyl-prolyl tRNA synthetase, and was likely to enhance translational efficiencies. A small interfering RNA against hDUS2 transfected into NSCLC cells suppressed expression of the gene, reduced the amount of dihydrouridine in tRNA molecules, and suppressed growth. Immunohistochemical analysis showed significant association between higher levels of hDUS2 in tumors and poorer prognosis of lung cancer patients. Our data imply that up-regulation of hDUS2 is a relatively common feature of pulmonary carcinogenesis and that selective suppression of hDUS2 enzyme activity and/or inhibition of formation of the hDUS2-tRNA synthetase complex could be a promising therapeutic strategy for treatment of many lung cancers.

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