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nonsense-mediated degradation

Karina Vexler, Miryam A Cymerman, Irina Berezin, Adi Fridman, Linoy Golani, Michal Lasnoy, Helen Saul, Orit Shaul
Nonsense-mediated mRNA decay (NMD) is a eukaryotic RNA surveillance mechanism that degrades aberrant transcripts and controls the levels of many normal mRNAs. It was shown that balanced expression of the NMD factor UPF3 is essential for the maintenance of proper NMD homeostasis in Arabidopsis. UPF3 expression is controlled by a negative feedback loop that exposes UPF3 transcript to NMD. It was shown that the long 3' untranslated region (3' UTR) of UPF3 exposes its transcript to NMD. Long 3' UTRs that subject their transcripts to NMD were identified in several eukaryotic NMD factors...
2016: Frontiers in Plant Science
Atsuko Miki, Josephine Galipon, Satoshi Sawai, Toshifumi Inada, Kunihiro Ohta
Antisense RNA has emerged as a crucial regulator of opposite-strand protein-coding genes in the long noncoding RNA (lncRNA) category, but little is known about their dynamics and decay process in the context of a stress response. Antisense transcripts from the fission yeast fbp1 locus (fbp1-as) are expressed in glucose-rich conditions and anticorrelated with transcription of metabolic stress-induced lncRNA (mlonRNA) and mRNA on the sense strand during glucose starvation. Here, we investigate the localization and decay of antisense RNAs at fbp1 and other loci, and propose a model to explain the rapid switch between antisense and sense mlonRNA/mRNA transcription triggered by glucose starvation...
October 10, 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Bijoyita Roy, Westley J Friesen, Yuki Tomizawa, John D Leszyk, Jin Zhuo, Briana Johnson, Jumana Dakka, Christopher R Trotta, Xiaojiao Xue, Venkateshwar Mutyam, Kim M Keeling, James A Mobley, Steven M Rowe, David M Bedwell, Ellen M Welch, Allan Jacobson
A premature termination codon (PTC) in the ORF of an mRNA generally leads to production of a truncated polypeptide, accelerated degradation of the mRNA, and depression of overall mRNA expression. Accordingly, nonsense mutations cause some of the most severe forms of inherited disorders. The small-molecule drug ataluren promotes therapeutic nonsense suppression and has been thought to mediate the insertion of near-cognate tRNAs at PTCs. However, direct evidence for this activity has been lacking. Here, we expressed multiple nonsense mutation reporters in human cells and yeast and identified the amino acids inserted when a PTC occupies the ribosomal A site in control, ataluren-treated, and aminoglycoside-treated cells...
October 4, 2016: Proceedings of the National Academy of Sciences of the United States of America
Kensuke Ninomiya, Mutsuhito Ohno, Naoyuki Kataoka
Localization of mRNA in neuronal cells is a critical process for spatiotemporal regulation of gene expression. Cytoplasmic localization of mRNA is often conferred by transport elements in 3' untranslated region (UTR). Activity-regulated cytoskeleton-associated protein (arc) mRNA is one of the localizing mRNAs in neuronal cells, and its localization is mediated by dendritic targeting element (DTE). As arc mRNA has introns in its 3' UTR, it was thought that arc mRNA is a natural target of nonsense-mediated mRNA decay (NMD)...
September 23, 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Megan G Behringer, David W Hall
Introns occasionally remain in mature mRNAs due to splicing errors and the translated, aberrant proteins that result represent a metabolic cost and may have other deleterious consequences. The nonsense-mediated decay pathway degrades aberrant mRNAs, which it recognizes by the presence of an in-frame premature termination codon. We investigated whether selection has shaped the location of premature termination codons in introns to reduce waste and facilitate nonsense-mediated decay. We found across seven model organisms, that in both first and last introns, premature termination codons occur earlier in introns than expected by chance, suggesting that selection favors earlier position...
September 14, 2016: Genetics
Rik G H Lindeboom, Fran Supek, Ben Lehner
Premature termination codons (PTCs) cause a large proportion of inherited human genetic diseases. PTC-containing transcripts can be degraded by an mRNA surveillance pathway termed nonsense-mediated mRNA decay (NMD). However, the efficiency of NMD varies; it is inefficient when a PTC is located downstream of the last exon junction complex (EJC). We used matched exome and transcriptome data from 9,769 human tumors to systematically elucidate the rules of NMD targeting in human cells. An integrated model incorporating multiple rules beyond the canonical EJC model explains approximately three-fourths of the non-random variance in NMD efficiency across thousands of PTCs...
October 2016: Nature Genetics
Vladyslav S Bondarenko, Mikhail S Gelfand
A typical eukaryotic gene is comprised of alternating stretches of regions, exons and introns, retained in and spliced out a mature mRNA, respectively. Although the length of introns may vary substantially among organisms, a large fraction of genes contains short introns in many species. Notably, some Ciliates (Paramecium and Nyctotherus) possess only ultra-short introns, around 25 bp long. In Paramecium, ultra-short introns with length divisible by three (3n) are under strong evolutionary pressure and have a high frequency of in-frame stop codons, which, in the case of intron retention, cause premature termination of mRNA translation and consequent degradation of the mis-spliced mRNA by the nonsense-mediated decay mechanism...
2016: PloS One
Vivek Kumar Raxwal, Karel Riha
Nonsense mediated RNA decay (NMD) is well-known as an RNA quality control mechanism that sequesters a substantial portion of RNA from expression by targeting it for degradation. However, a number of recent studies across a range of organisms indicate a broader role for NMD in gene regulation and transcriptome homeostasis. Here we propose a novel role for NMD as a buffering system with the capability of accumulating and subsequently releasing a wide spectrum of cryptic genetic variation in response to environmental stimuli, and hence facilitating adaptive evolution...
September 4, 2016: Biochimica et Biophysica Acta
Sébastien Durand, Tobias M Franks, Jens Lykke-Andersen
Many gene expression factors contain repetitive phosphorylation sites for single kinases, but the functional significance is poorly understood. Here we present evidence for hyperphosphorylation as a mechanism allowing UPF1, the central factor in nonsense-mediated decay (NMD), to increasingly attract downstream machinery with time of residence on target mRNAs. Indeed, slowing NMD by inhibiting late-acting factors triggers UPF1 hyperphosphorylation, which in turn enhances affinity for factors linking UPF1 to decay machinery...
2016: Nature Communications
Christian Hauer, Jana Sieber, Thomas Schwarzl, Ina Hollerer, Tomaz Curk, Anne-Marie Alleaume, Matthias W Hentze, Andreas E Kulozik
The exon junction complex (EJC) connects spliced mRNAs to posttranscriptional processes including RNA localization, transport, and regulated degradation. Here, we provide a comprehensive analysis of bona fide EJC binding sites across the transcriptome including all four RNA binding EJC components eIF4A3, BTZ, UPF3B, and RNPS1. Integration of these data sets permits definition of high-confidence EJC deposition sites as well as assessment of whether EJC heterogeneity drives alternative nonsense-mediated mRNA decay pathways...
August 9, 2016: Cell Reports
Yi Jin, Fang Zhang, Zhenfa Ma, Zhuqing Ren
BACKGROUND: Nonsense-mediated mRNA decay (NMD) is a RNA quality surveillance system for eukaryotes. It prevents cells from generating deleterious truncated proteins by degrading abnormal mRNAs that harbor premature termination codon (PTC). However, little is known about the molecular regulation mechanism underlying the inhibition of NMD by microRNAs. RESULTS: The present study demonstrated that miR-433 was involved in NMD pathway via negatively regulating SMG5. We provided evidence that (1) overexpression of miR-433 significantly suppressed the expression of SMG5 (P < 0...
2016: BMC Molecular Biology
Helena C Fabbri, Juliana G Ribeiro de Andrade, Andréa T Maciel-Guerra, Gil Guerra-Júnior, Maricilda P de Mello
Mutations in the NR5A1 gene, which encodes the steroidogenic factor 1 (SF1), are responsible for different phenotypes of disorders of sex development (DSD), such as bilateral anorchia and hypospadias. Furthermore, they can be associated with primary amenorrhea, premature ovarian failure, male infertility, adrenal tumors, and endometriosis. Direct sequencing of the 7 NR5A1 exons including ∼1,000 bp of the 5'-upstream and 3'-downstream regions and all intron-exon boundaries was performed in patients with DSD...
2016: Sexual Development: Genetics, Molecular Biology, Evolution, Endocrinology, Embryology, and Pathology of Sex Determination and Differentiation
Hongwei Luo, Lauren Cowen, Guowu Yu, Wenguo Jiang, Yi Tang
The p53 tumor suppressor functions as a transcription factor and plays a pivotal role in regulation of cellular response to DNA damage by activating various genes including those involved in cell cycle arrest. p53 stability is essential for its function during stress response; however, the molecular mechanism for DNA damage-induced stabilization of p53 is not fully understood. In our present study, we have identified SMG7 (suppressor with morphological defects in genitalia 7), also known as EST1C, as a novel p53-binding protein...
2016: Cell Discovery
Jing-Qiong Kang, Robert L Macdonald
OBJECTIVE: In this review article, we focus on the molecular pathogenic basis for genetic generalized epilepsies associated with mutations in the inhibitory γ-aminobutyric acid (GABAA) receptor γ2 subunit gene, GABRG2 (OMIM 137164), an established epilepsy gene. OBSERVATIONS: The γ-aminobutyric acid (GABAA) receptor γ2 subunit gene, GABRG2, is abundantly expressed in the mammalian brain, and its encoded γ2 subunit is assembled into αβγ2 receptors, which are the major GABAA receptor isoforms in the brain...
August 1, 2016: JAMA Neurology
Chih-Hong Lou, Jennifer Dumdie, Alexandra Goetz, Eleen Y Shum, David Brafman, Xiaoyan Liao, Sergio Mora-Castilla, Madhuvanthi Ramaiah, Heidi Cook-Andersen, Louise Laurent, Miles F Wilkinson
Nonsense-mediated RNA decay (NMD) is a highly conserved pathway that selectively degrades specific subsets of RNA transcripts. Here, we provide evidence that NMD regulates early human developmental cell fate. We found that NMD factors tend to be expressed at higher levels in human pluripotent cells than in differentiated cells, raising the possibility that NMD must be downregulated to permit differentiation. Loss- and gain-of-function experiments in human embryonic stem cells (hESCs) demonstrated that, indeed, NMD downregulation is essential for efficient generation of definitive endoderm...
June 14, 2016: Stem Cell Reports
Benjamin Kolisnyk, Mohammed A Al-Onaizi, Jason Xu, Gustavo M Parfitt, Valeriy G Ostapchenko, Geula Hanin, Hermona Soreq, Marco A M Prado, Vania F Prado
UNLABELLED: Cholinergic vulnerability, characterized by loss of acetylcholine (ACh), is one of the hallmarks of Alzheimer's disease (AD). Previous work has suggested that decreased ACh activity in AD may contribute to pathological changes through global alterations in alternative splicing. This occurs, at least partially, via the regulation of the expression of a critical protein family in RNA processing, heterogeneous nuclear ribonucleoprotein (hnRNP) A/B proteins. These proteins regulate several steps of RNA metabolism, including alternative splicing, RNA trafficking, miRNA export, and gene expression, providing multilevel surveillance in RNA functions...
June 8, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Sridevi Sureshkumar, Craig Dent, Andrei Seleznev, Celine Tasset, Sureshkumar Balasubramanian
Increasing global temperatures have an impact on flowering, and the underlying mechanisms are just beginning to be unravelled(1,2). Elevated temperatures can induce flowering, and different mechanisms that involve either activation or de-repression of FLOWERING LOCUS T (FT) by transcription factor PHYTOCHROME INTERACTING FACTOR 4 (PIF4) or the FLOWERING LOCUS M (FLM)-SHORT VEGETATIVE PHASE (SVP) complex, respectively, have been suggested to be involved(3-6). Thermosensitivity in flowering has been mapped to FLM(5), which encodes a floral repressor(7,8)...
2016: Nature Plants
N G Gurskaya, A P Pereverzev, D B Staroverov, N M Markina, K A Lukyanov
Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved mechanism of specific degradation of transcripts with a premature stop codon. NMD eliminates aberrant mRNAs arising from mutations, alternative splicing, and other events in cells. In addition, many normal transcripts undergo NMD. Recent studies demonstrated that NMD activity is specifically regulated and that NMD can play a role of global regulator of gene expression. Recently, we developed dual-color fluorescent protein-based reporters for quantification of NMD activity using fluorescence microscopy and flow cytometry (Pereverzev, Gurskaya, et al...
2016: Methods in Enzymology
Carrie L Simms, Erica N Thomas, Hani S Zaher
Quality control processes are widespread and play essential roles in detecting defective molecules and removing them in order to maintain organismal fitness. Aberrant messenger RNA (mRNA) molecules, unless properly managed, pose a significant hurdle to cellular proteostasis. Often mRNAs harbor premature stop codons, possess structures that present a block to the translational machinery, or lack stop codons entirely. In eukaryotes, the three cytoplasmic mRNA-surveillance processes, nonsense-mediated decay (NMD), no-go decay (NGD), and nonstop decay (NSD), evolved to cope with these aberrant mRNAs, respectively...
May 18, 2016: Wiley Interdisciplinary Reviews. RNA
Jianqiang Bao, Kristoffer Vitting-Seerup, Johannes Waage, Chong Tang, Ying Ge, Bo T Porse, Wei Yan
During transcription, most eukaryotic genes generate multiple alternative cleavage and polyadenylation (APA) sites, leading to the production of transcript isoforms with variable lengths in the 3' untranslated region (3'UTR). In contrast to somatic cells, male germ cells, especially pachytene spermatocytes and round spermatids, express a distinct reservoir of mRNAs with shorter 3'UTRs that are essential for spermatogenesis and male fertility. However, the mechanisms underlying the enrichment of shorter 3'UTR transcripts in the developing male germ cells remain unknown...
May 2016: PLoS Genetics
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