Ribosome Modulation Research Articles

SigR, a hub of multilayered regulation of redox and antibiotic stress responses.

Signal-specific activation of alternative sigma factors redirects RNA polymerase to induce transcription of distinct sets of genes conferring protection against the damage the signal and the related stresses incur. In Streptomyces coelicolor, σR (SigR), a member of ECF12 subfamily of Group IV sigma factors, responds to thiol-perturbing signals such as oxidants and electrophiles, as well as to translation-blocking antibiotics. Oxidants and electrophiles interact with and inactivate the zinc-containing anti-sigma factor, RsrA, via disulfide bond formation or alkylation of reactive cysteines, subsequently releasing σR for target gene induction. Translation-blocking antibiotics induce the synthesis of σR , via the WhiB-like transcription factor, WblC/WhiB7. Signal transduction via RsrA produces a dramatic transient response that involves positive feedback to produce more SigR as an unstable isoform and negative feedbacks to degrade , and reduce oxidized RsrA that subsequently sequester σR and . Antibiotic stress brings about a prolonged response by increasing stable σR levels. The third negative feedback, which occurs via IF3, lowers the translation efficiency of the sigRp1 transcript that utilizes a non-canonical start codon. σR is a global regulator that directly activates > 100 transcription units in S. coelicolor, including genes for thiol homeostasis, protein quality control, sulfur metabolism, ribosome modulation and DNA repair. Close homologues in Actinobacteria, such as σH in Mycobacteria and Corynebacteria, show high conservation of the signal transduction pathways and target genes, thus reflecting the robustness of this type of regulation in response to redox and antibiotic stresses.

Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation.

Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a Tal1/Lmo1/Notch1-driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression. SIGNIFICANCE: The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome-mitochondria axis, suggesting the potential for therapeutic intervention.This article is highlighted in the In This Issue feature, p. 1494.

Conservation of thiol‐oxidative stress responses regulated by SigR orthologues in actinomycetes

Numerous thiol-reactive compounds cause oxidative stress where cells counteract by activation of survival strategies regulated by thiol-based sensors. In Streptomyces coelicolor, a model actinomycete, a sigma/antisigma pair SigR/RsrA controls the response to thiol-oxidative stress. To unravel its full physiological functions, chromatin immuno-precipitation combined with sequence and transcript analyses were employed to identify 108 SigR target genes in S. coelicolor and to predict orthologous regulons across actinomycetes. In addition to reported genes for thiol homeostasis, protein degradation and ribosome modulation, 64 additional operons were identified suggesting new functions of this global regulator. We demonstrate that SigR maintains the level and activity of the housekeeping sigma factor HrdB during thiol-oxidative stress, a novel strategy for stress responses. We also found that SigR defends cells against UV and thiol-reactive damages, in which repair UvrA takes a part. Using a refined SigR-binding sequence model, SigR orthologues and their targets were predicted in 42 actinomycetes. This revealed a conserved core set of SigR targets to function for thiol homeostasis, protein quality control, possible modulation of transcription and translation, flavin-mediated redox reactions, and Fe-S delivery. The composition of the SigR regulon reveals a robust conserved physiological mechanism to deal with thiol-oxidative stress from bacteria to human.