🧬 PubMed RNase III Daily Digest

RNA interference (RNAi) depends on DICER, an essential enzyme that processes RNA precursors into small regulatory RNAs. DICER cleaves RNA precursors according to the 5'-end counting rule, in which RNA length is measured from the 5'-end

Nuclear microRNAs represent a novel class of non-canonical miRNAs localized within the nucleus, distinguished from classical cytoplasmic miRNAs by their unique ability to activate gene transcription. Classical miRNAs, approximately 22 nucleotides in length, regulate target mRNA stability or translational efficiency, primarily leading to translation inhibition or mRNA degradation. In contrast, nuclear microRNAs, measuring 18-22 nucleotides, do not rely on Dicer processing and are directly cleaved from precursor miRNAs by Drosha. Their nuclear localization and regulation of gene transcription contrast sharply with the suppressive role of classical miRNAs. Nuclear microRNAs are transcribed and modified within the nucleus via RNA polymerase II, undergoing processing similar to conventional miRNAs but diverging in their final nuclear localization and functional mechanisms. They interact with key regulatory elements such as promoters, enhancers, or gene bodies, modulating gene expression at the transcriptional level. This interaction can occur through RNA-RNA scaffolding, RNA-DNA hybrid formation, or RNA-DNA triplex formation, influencing chromatin structure and transcription factor accessibility. Nuclear microRNAs demonstrate diverse regulatory functions, acting as enhancer triggers, promoter regulators, and transcriptional amplifiers. They recruit transcription factors or alter chromatin's epigenetic state to promote transcription, impacting cellular processes such as hematopoiesis, differentiation, and apoptosis. In particular, nuclear microRNAs have been implicated in cancer progression and therapeutic responses, with the potential to orchestrate oncogene networks and tumor-suppressive pathways. Despite their promising therapeutic potential, clinical translation of nuclear microRNAs faces challenges such as delivery precision, immunogenicity, regulatory complexity, and ethical governance. Advancing nuclear delivery systems and mechanistic studies are essential to overcome these limitations and harness the full potential of nuclear microRNAs in gene regulation therapeutics. As research progresses, nuclear microRNAs may revolutionize RNA therapeutics by enabling transcriptional-level disease intervention.

Pleuropulmonary blastoma (PPB) is a rare primary lung neoplasm predominantly occurring in infancy and early childhood, which, because of rarity and/or confusion with congenital cystic lung lesions and its variable architectural and morphologic features, can be a diagnostic challenge. To characterize the diagnostic challenges in cases submitted to the International PPB/DICER1 [dicer 1, ribonuclease III] Registry (Registry) with a possible PPB diagnosis. This study reviews lesions submitted to the Registry during a 35-year period. Pathologic diagnoses, ancillary studies, and genetic information were reviewed. Of the 868 thoracic tumors submitted to the Registry from 1987 to 2022, 79% (685 of 868) were confirmed as PPB by central review. In the remaining 21% (183 of 868) of cases, PPB was either excluded or could not be confirmed with available material. Most of these cases (64%; 117 of 183) were malignant; 31% (56 of 183) were benign, and 5% (10 of 183) were of uncertain malignant potential. The most common benign discrepant diagnosis was congenital pulmonary airway malformation (n = 19), and the most common malignant discrepant or indeterminate diagnosis was rhabdomyosarcoma, including sarcoma with rhabdomyoblastic differentiation (n = 24). DICER1 RNase IIIb hotspot variants were detected by tumor testing in 4 cases with histology discrepant from or inconclusive for classical PPB. Additionally, 4 patients with non-PPB histology were found to have a germline DICER1 pathogenic or likely pathogenic variant without available tumor testing. The histomorphologic heterogeneity of PPB resulted in a variety of non-PPB diagnoses among cases not initially classified as PPB. Molecular testing may clarify the diagnosis and provide prognostic and therapeutic insights.

We investigated whether liver disease alters HSD17B13 isoform expression, identifying selective loss of exon 2-skipped variants and uncovering variant B as a structured, noncoding RNA with silencing potential. Human liver samples from lean control (n = 6), metabolic dysfunction-associated steatotic liver (MASL, n = 8), and metabolic dysfunction-associated steatohepatitis (MASH, n = 8) participants were analyzed by isoform-specific reverse-transcription PCR and quantitative PCR. HepG2 cells were transfected with HSD17B13 variant A or B constructs. RNA expression, protein production, RNase sensitivity, and RNA structural conformations (RNAfold) were evaluated. Functional effects were tested under oleic acid-induced lipotoxic stress. We observed a selective reduction in exon 2-skipped HSD17B13 isoforms (variants B and G) in both human MASL (∼63% vs. lean control; p <0.01) and MASH (∼93% vs. lean control; p <0.001), independent of rs72613567:TA genotype. Notably, variant B nearly abolished endogenous HSD17B13 expression in HepG2 cells (∼99% reduction; p <0.001) without generating detectable protein. RNase III sensitivity assays and RNAfold modeling revealed stable, duplex-rich RNA structures, supporting a noncoding regulatory role for these isoforms under oleic acid-induced lipotoxic stress. Restoration of exon 2-skipped HSD17B13 isoforms, particularly variant B, may offer a genotype-independent therapeutic strategy for MASH by mimicking protective effects through structured RNA-mediated suppression of enzymatic HSD17B13 activity. These findings support a dual mechanism of HSD17B13 regulation in liver disease through genotype-mediated transcript suppression and disease-driven isoform imbalance. Therapeutic re-expression of exon 2-skipped isoforms, particularly variant B, may offer a novel strategy to replicate the protective effect of the TA allele without enzymatic inhibition.

During SARS-CoV-2 infection, the key protective oligoadenylate synthetase (OAS) that activates RNase L upon sensing viral dsRNA is the membrane-anchored OAS1 isoform p46. We show that SARS-CoV-2 3C-like main protease (3CL