Human sat III and Drosophila hsrω transcripts: a common paradigm for regulation of nuclear RNA processing in stressed cells

Exposure of cells to stressful conditions elicits a highly conserved defense mechanism termed the heat shock response, resulting in the production of specialized proteins which protect the cells against the deleterious effects of stress. The heat shock response involves not only a widespread inhibition of the ongoing transcription and activation of heat shock genes, but also important changes in post-transcriptional processing. In particular, a blockade in splicing and other post-transcriptional processing has been described following stress in different organisms, together with an altered spatial distribution of the proteins involved in these activities. However, the specific mechanisms that regulate these activities under conditions of stress are little understood. Non-coding RNA molecules are increasingly known to be involved in the regulation of various activities in the cell, ranging from chromatin structure to splicing and RNA degradation. In this review, we consider two non-coding RNAs, the hsrω transcripts in Drosophila and the sat III transcripts in human cells, that seem to be involved in the dynamics of RNA-processing factors in normal and/or stressed cells, and thus provide new paradigms for understanding transcriptional and post-transcriptional regulations in normal and stressed cells

Accumulation of poly(A) RNA in nuclear granules enriched in Sam68 in motor neurons from the SMNA7 mouse model of SMA

Spinal muscular atrophy (SMA) is a severe motor neuron (MN) disease caused by the deletion or mutation of the survival motor neuron 1 (SMN1) gene, which results in reduced levels of the SMN protein and the selective degeneration of lower MNs. The best-known function of SMN is the biogenesis of spliceosomal snRNPs, the major components of the pre-mRNA splicing machinery. Therefore, SMN deficiency in SMA leads to widespread splicing abnormalities. We used the SMN?7 mouse model of SMA to investigate the cellular reorganization of polyadenylated mRNAs associated with the splicing dysfunction in MNs. We demonstrate that SMN deficiency induced the abnormal nuclear accumulation in euchromatin domains of poly(A) RNA granules (PARGs) enriched in the splicing regulator Sam68. However, these granules lacked other RNA-binding proteins, such as TDP43, PABPN1, hnRNPA12B, REF and Y14, which are essential for mRNA processing and nuclear export. These effects were accompanied by changes in the alternative splicing of the Sam68-dependent Bcl-x and Nrnx1 genes, as well as changes in the relative accumulation of the intron-containing Chat, Chodl, Myh9 and Myh14 mRNAs, which are all important for MN functions. PARG-containing MNs were observed at presymptomatic SMA stage, increasing their number during the symptomatic stage. Moreover, the massive accumulations of poly(A) RNA granules in MNs was accompanied by the cytoplasmic depletion of polyadenylated mRNAs for their translation. We suggest that the SMN-dependent abnormal accumulation of polyadenylated mRNAs and Sam68 in PARGs reflects a severe dysfunction of both mRNA processing and translation, which could contribute to SMA pathogenesis.This work was supported by grants from: “Dirección General de Investigación” of Spain (BFU2014-54754-P and SAF2015-70801-R, cofinanced by FEDER) and “Instituto de Investigación Marqués de Valdecilla-IDIVAL (NVAL17/22). Dr. Tapia is the recipient of a grant from SMA Europe and FundAME (Spain)

Long non-coding RNAs: spatial amplifiers that control nuclear structure and gene expression

Over the past decade, it has become clear that mammalian genomes encode thousands of long non-coding RNAs (lncRNAs), many of which are now implicated in diverse biological processes. Recent work studying the molecular mechanisms of several key examples — including Xist, which orchestrates X chromosome inactivation — has provided new insights into how lncRNAs can control cellular functions by acting in the nucleus. Here we discuss emerging mechanistic insights into how lncRNAs can regulate gene expression by coordinating regulatory proteins, localizing to target loci and shaping three-dimensional (3D) nuclear organization. We explore these principles to highlight biological challenges in gene regulation, in which lncRNAs are well-suited to perform roles that cannot be carried out by DNA elements or protein regulators alone, such as acting as spatial amplifiers of regulatory signals in the nucleus

Heterogeneous nuclear ribonucleoproteins (hnRNPs): An emerging family of autoantigens in rheumatic diseases

In eukaryotic cells, mature mRNA molecules are produced through the extensive post-transcriptional processing of primary transcripts assembled in ribonucleoprotein complexes. Twenty polypeptides, termed heterogeneous nuclear ribonucleoproteins or hnRNPs, have been identified as the major components of such complexes. Although these proteins were identified more than 30 years ago, their role in RNA metabolism is just beginning to emerge. In contrast to previous models that ascribed to hnRNPs a mere structural function, recent data suggest a direct involvement in several aspects of the RNA life, such splicing, export of the mature mRNAs to the cell cytoplasm and translation. In addition, a growing body of evidence points to hnRNPs as an important target of the autoimmune response in rheumatic diseases. The present paper will review some of the most relevant data concerning the structure, function and autoantigenic properties of the hnRNPs

Heterogeneous nuclear ribonucleoproteins (hnRNPs): An emerging family of autoantigens in rheumatic diseases

In eukaryotic cells, mature mRNA molecules are produced through the extensive post-transcriptional processing of primary transcripts assembled in ribonucleoprotein complexes. Twenty polypeptides, termed heterogeneous nuclear ribonucleoproteins or hnRNPs, have been identified as the major components of such complexes. Although these proteins were identified more than 30 years ago, their role in RNA metabolism is just beginning to emerge. In contrast to previous models that ascribed to hnRNPs a mere structural function, recent data suggest a direct involvement in several aspects of the RNA life, such splicing, export of the mature mRNAs to the cell cytoplasm and translation. In addition, a growing body of evidence points to hnRNPs as an important target of the autoimmune response in rheumatic diseases. The present paper will review some of the most relevant data concerning the structure, function and autoantigenic properties of the hnRNPs