RESUMEN
Thiolutin is a disulfide-containing antibiotic and anti-angiogenic compound produced by Streptomyces. Its biological targets are not known. We show that reduced thiolutin is a zinc chelator that inhibits the JAB1/MPN/Mov34 (JAMM) domain-containing metalloprotease Rpn11, a deubiquitinating enzyme of the 19S proteasome. Thiolutin also inhibits the JAMM metalloproteases Csn5, the deneddylase of the COP9 signalosome; AMSH, which regulates ubiquitin-dependent sorting of cell-surface receptors; and BRCC36, a K63-specific deubiquitinase of the BRCC36-containing isopeptidase complex and the BRCA1-BRCA2-containing complex. We provide evidence that other dithiolopyrrolones also function as inhibitors of JAMM metalloproteases.
Asunto(s)
Quelantes/farmacología , Inhibidores Enzimáticos/farmacología , Metaloproteasas/antagonistas & inhibidores , Transactivadores/antagonistas & inhibidores , Zinc/química , Quelantes/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Células HeLa , Humanos , Metaloproteasas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Pirrolidinonas/química , Pirrolidinonas/metabolismo , Pirrolidinonas/farmacología , Relación Estructura-Actividad , Transactivadores/metabolismoRESUMEN
After publication of the original article [1], the authors noted that Additional files 6, 8 and 9 and their legends were incorrect.
RESUMEN
BACKGROUND: Long non protein coding RNAs (lncRNAs) have been identified in many different organisms and cell types. Emerging examples emphasize the biological importance of these RNA species but their regulation and functions remain poorly understood. In the filamentous fungus Neurospora crassa, the annotation and characterization of lncRNAs is incomplete. RESULTS: We have performed a comprehensive transcriptome analysis of Neurospora crassa by using ChIP-seq, RNA-seq and polysome fractionation datasets. We have annotated and characterized 1478 long intergenic noncoding RNAs (lincRNAs) and 1056 natural antisense transcripts, indicating that 20% of the RNA Polymerase II transcripts of Neurospora are not coding for protein. Both classes of lncRNAs accumulate at lower levels than protein-coding mRNAs and they are considerably shorter. Our analysis showed that the vast majority of lincRNAs and antisense transcripts do not contain introns and carry less H3K4me2 modifications than similarly expressed protein coding genes. In contrast, H3K27me3 modifications inversely correlate with transcription of protein coding and lincRNA genes. We show furthermore most lincRNA sequences evolve rapidly, even between phylogenetically close species. CONCLUSIONS: Our transcriptome analyses revealed distinct features of Neurospora lincRNAs and antisense transcripts in comparison to mRNAs and showed that the prevalence of noncoding transcripts in this organism is higher than previously anticipated. The study provides a broad repertoire and a resource for further studies of lncRNAs.