Dihydrouridine synthase 2 (DUS2)

Dihydrouridine synthase 2 (DUS2) is a cytoplasmic, flavin-dependent enzyme that catalyzes the NADPH-dependent reduction of uridine to dihydrouridine at position 20 of cytoplasmic tRNAs[3][5]. This modification increases structural flexibility of tRNA, affecting translation efficiency and possibly cellular stress responses[1][2][3]. Beyond its canonical role in tRNA modification, DUS2 interacts with and can inhibit protein kinase R (EIF2AK2/PKR), and its up-regulation is linked to pulmonary carcinogenesis and other cancers[3][5]. DUS2 contains a TIM-barrel catalytic domain, a helical domain, and a unique double-stranded RNA-binding domain (dsRBD) crucial for tRNA recognition and binding in higher eukaryotes[1][5]. Alterations or overexpression of DUS2 have been implicated in cancer cell proliferation and, potentially, in neurodegenerative processes[1][3]. No approved drugs directly target DUS2, but small molecule inhibitors have been identified in preclinical studies[4]. Functional and structural specificity: - DUS2 is highly specific for modifying uridine 20 (U20) in tRNA and requires a minimal GU sequence in the tRNA D-loop for substrate recognition[4]. - Its overexpression can enhance protein synthesis by limiting activation of stress response protein kinases[3]. Clinical significance: - DUS2’s up-regulation in lung cancer makes it a potential biomarker and a candidate for anticancer therapeutic intervention[3][4]. - Modulating its activity may impact translational regulation and cell proliferation[3]. Safety concerns: Targeting DUS2 may pose risks to normal cellular processes due to its essential role in tRNA function and protein synthesis, and off-target effects could have broad, systemic consequences[4]. Summary: Dihydrouridine synthase 2 (DUS2) is an enzyme central to tRNA modification, implicated in cancer biology and translational regulation, with ongoing research exploring its value as a drug target and clinical biomarker.

Other names

tRNA-dihydrouridine(20) synthase [NAD(P)+]-likeDUS2LURLC8hDUS2FLJ20399SMM1up-regulated in lung cancer protein 8tRNA-dihydrouridine synthase 2-likeSMM1 homolog (S. cerevisiae)SMM1 homologdihydrouridine synthase 2-like

Inhibitors block NADPH-dependent reduction of uridine to dihydrouridine in tRNA; potential anticancer effect via inhibition of tRNA modification or suppression of EIF2AK2/PKR kinase[3][4].