The human tRNA-modifying protein, TRIT1, forms amyloid fibers in vitro.

TRIT1 is a highly conserved tRNA isopentenyl transferase that modifies a subset of tRNAs in human cells and is a candidate tumor suppressor in lung cancer in certain ethnic populations. The yeast homologue, Mod5, has similar tRNA-modifying functions in the cytoplasm and is required for the transcriptional silencing activity of RNA polymerase II promoters near tRNA genes in the nucleus, a phenomenon termed tRNA gene mediated (tgm) silencing. Furthermore, Mod5 can fold into amyloid fibers in vitro and in vivo, which confers resistance to certain fungicides in yeast. Since TRIT1 complements both tRNA modifying and tgm-silencing activities in yeast where the Mod5 gene has been deleted, it seemed possible that TRIT1 might also have amyloid-forming capabilities. Here we show that TRIT1, like Mod5, directly binds to tRNAs that are both substrate and non-substrates for modification with similar affinity, and to an unstructured, non-tRNA. Binding appears to involve distinct protein-RNA multimers which decrease in electrophoretic mobility as the protein to RNA ratio increases. Furthermore, we characterize TRIT1 as a novel human amyloid fiber forming protein. We discuss these data in light of TRIT1's functional roles and possible implications for disease.

Reduction in sudden death and total mortality by antiarrhythmic therapy evaluated by electrophysiologic drug testing: criteria of efficacy in patients with sustained ventricular tachyarrhythmia.

Reports of the results of electrophysiologic testing of antiarrhythmic regimens have concentrated on inducibility of ventricular tachycardias during drug treatment. Many drug regimens, however, affect the tachycardia but fail to prevent its initiation. In this study, 258 patients who underwent serial electrophysiologic studies were followed up. The patients were divided into three groups on the basis of the results of electrophysiologic testing. Group 1 included patients in whom the initiation of ventricular tachycardia was prevented by the drug regimen. In groups 2 and 3 the ventricular tachycardia was still inducible with the discharge drug regimen. In group 2, the drug regimen demonstrated a beneficial response (that is, the tachycardia cycle length increased by greater than 100 ms and the tachycardia did not produce severe symptoms). In group 3, the regimen did not produce a beneficial response. During follow-up, recurrence of sustained ventricular tachycardia occurred in 7 (7%) of 103 group 1 patients but in 20 (39%) of 51 and 52 (50%) of 104 group 2 and 3 patients, respectively. However, the total mortality and sudden death mortality rates were substantially reduced in group 2 (12 and 4%, respectively) compared with group 3 (39 and 34%). In fact, the total mortality and sudden death mortality in groups 1 and 2 were not significantly different. Thus, under certain circumstances, a drug regimen that produces a beneficial response may be an acceptable clinical alternative, particularly when no regimen prevents induction of ventricular tachycardia.