scholarly journals Sequential regulation of maternal mRNAs through a conserved cis-acting element in their 3’UTRs

2018 ◽  
Author(s):  
Pooja Flora ◽  
Siu Wah Wong-Deyrup ◽  
Elliot Todd Martin ◽  
Ryan J Palumbo ◽  
Mohamad Nasrallah ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Polar Granule ◽  
Regulatory Sequence ◽  
Cis Acting ◽  
Maternal Mrna ◽  
Hand Off ◽  
Maternal Mrnas ◽  
Translational Regulators ◽  
Regulatory Landscape

AbstractMaternal mRNAs are synthesized during oogenesis to initiate the development of future generations. Some maternal mRNAs are determinants of somatic or germline fate and must be translationally repressed until embryogenesis. However, the translational repressors themselves are also temporally regulated. We use polar granule component (pgc), a Drosophila maternal mRNA, as a model system to ask how maternal mRNAs are repressed while the regulatory landscape is continually shifting. pgc, a potent transcriptional silencer and germline determinant, is translationally regulated throughout oogenesis. We find that the 3’UTR of pgc mRNA contains a conserved ten-nucleotide sequence that is bound by different conserved RNA binding proteins (RBPs) at different stages of oogenesis to continuously repress translation except for a brief expression in the stem cell daughter. Pumilio (Pum) binds to this sequence in undifferentiated and early differentiating oocytes and recruits other temporally restricted translational regulators to block pgc translation. After differentiation, Pum levels diminish and Bruno (Bru) levels increase, allowing Bru to bind the same 3’UTR sequence and take over translational repression of pgc mRNA. We have identified a class of maternal mRNAs regulated during oogenesis by both Pum and Bru, including Zelda, activator of the zygotic genome, which contain this core 10-nt regulatory sequence. Our data suggests that this hand off mechanism is more generally utilized to inhibit translation of maternal mRNAs during oogenesis.

scholarly journals Comprehensive landscape and future perspectives of circular RNAs in colorectal cancer

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Fei Long ◽  
Zhi Lin ◽  
Liang Li ◽  
Min Ma ◽  
Zhixing Lu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Circular Rnas ◽  
Future Perspectives ◽  
Cis Acting ◽  
New Class ◽  
Functional Peptides ◽  
Mirna Sponges

AbstractColorectal cancer (CRC) is a common hereditary tumor that is often fatal. Its pathogenesis involves multiple genes, including circular RNAs (circRNAs). Notably, circRNAs constitute a new class of noncoding RNAs (ncRNAs) with a covalently closed loop structure and have been characterized as stable, conserved molecules that are abundantly expressed in tissue/development-specific patterns in eukaryotes. Based on accumulating evidence, circRNAs are aberrantly expressed in CRC tissues, cells, exosomes, and blood from patients with CRC. Moreover, numerous circRNAs have been identified as either oncogenes or tumor suppressors that mediate tumorigenesis, metastasis and chemoradiation resistance in CRC. Although the regulatory mechanisms of circRNA biogenesis and functions remain fairly elusive, interesting results have been obtained in studies investigating CRC. In particular, the expression of circRNAs in CRC is comprehensively modulated by multiple factors, such as splicing factors, transcription factors, specific enzymes and cis-acting elements. More importantly, circRNAs exert pivotal effects on CRC through various mechanisms, including acting as miRNA sponges or decoys, interacting with RNA binding proteins, and even translating functional peptides. Finally, circRNAs may serve as promising diagnostic and prognostic biomarkers and potential therapeutic targets in the clinical practice of CRC. In this review, we discuss the dysregulation, functions and clinical significance of circRNAs in CRC and further discuss the molecular mechanisms by which circRNAs exert their functions and how their expression is regulated. Based on this review, we hope to reveal the functions of circRNAs in the initiation and progression of cancer and highlight the future perspectives on strategies targeting circRNAs in cancer research.

scholarly journals Defective control of pre–messenger RNA splicing in human disease

2016 ◽  
Vol 212 (1) ◽  
pp. 13-27 ◽  
Author(s):  
Benoit Chabot ◽  
Lulzim Shkreta
Keyword(s):  
Alternative Splicing ◽  
Human Disease ◽  
Rna Splicing ◽  
Messenger Rna ◽  
Recent Progress ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulatory Proteins ◽  
Regulatory Sequence ◽  
Sequence Elements

Examples of associations between human disease and defects in pre–messenger RNA splicing/alternative splicing are accumulating. Although many alterations are caused by mutations in splicing signals or regulatory sequence elements, recent studies have noted the disruptive impact of mutated generic spliceosome components and splicing regulatory proteins. This review highlights recent progress in our understanding of how the altered splicing function of RNA-binding proteins contributes to myelodysplastic syndromes, cancer, and neuropathologies.

scholarly journals Programmable mammalian translational modulators by CRISPR-associated proteins

2021 ◽  
Author(s):  
Shunsuke Kawasaki ◽  
Hiroki Ono ◽  
Moe Hirosawa ◽  
Takeru Kuwabara ◽  
Hirohide Saito
Keyword(s):  
Mammalian Cells ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Genetic Circuits ◽  
Genomic Engineering ◽  
Associated Proteins ◽  
Translational Regulators ◽  
Rna Motif ◽  
Cas Proteins

The complexity of synthetic genetic circuits relies on repertories of biological circuitry with high orthogonality. Although post-transcriptional circuitry relying on RNA-binding proteins (RBPs) qualifies as a repertory, the limited pool of regulatory devices hinders network modularity and scalability. Here we propose CaRTRIDGE (Cas-Responsive Translational Regulation Integratable into Diverse Genomic Engineering) to repurpose CRISPR-associated (Cas) proteins as translational modulators. We demonstrate that a set of Cas proteins are able to repress (OFF) or activate (ON) the translation of mRNAs that contain a Cas-binding RNA motif in the 5'-UTR. We designed 81 different types of translation OFF and ON switches and verified their functional characteristics. Many of them functioned as efficient translational regulators and showed orthogonality in mammalian cells. By interconnecting these switches, we designed and built artificial circuits, including 60 translational AND gates. Moreover, we show that various CRISPR-related technologies, including anti-CRISPR and split-Cas9 platforms, can be repurposed to control translation. Our Cas-mediated translational regulation is compatible with transcriptional regulation by Cas proteins and increases the complexity of synthetic circuits with fewer elements. CaRTRIDGE builds protein-responsive mRNA switches more than ever and leads to the development of both Cas-mediated genome editing and translational regulation technologies.

Increased expression of utrophin in a slow vs. a fast muscle involves posttranscriptional events

2001 ◽  
Vol 281 (4) ◽  
pp. C1300-C1309 ◽  
Author(s):  
Anthony O. Gramolini ◽  
Guy Bélanger ◽  
Jennifer M. Thompson ◽  
Joe V. Chakkalakal ◽  
Bernard J. Jasmin
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Synaptic Proteins ◽  
Structural Protein ◽  
Rt Pcr ◽  
Western Blots ◽  
Cis Acting ◽  
Fast And Slow Muscles ◽  
Parallel Increase

In addition to showing differences in the levels of contractile proteins and metabolic enzymes, fast and slow muscles also differ in their expression profile of structural and synaptic proteins. Because utrophin is a structural protein expressed at the neuromuscular junction, we hypothesize that its expression may be different between fast and slow muscles. Western blots showed that, compared with fast extensor digitorum longus (EDL) muscles, slow soleus muscles contain significantly more utrophin. Quantitative RT-PCR revealed that this difference is accompanied by a parallel increase in the expression of utrophin transcripts. Interestingly, the higher levels of utrophin and its mRNA appear to occur in extrasynaptic regions of muscle fibers as shown by immunofluorescence and in situ hybridization experiments. Furthermore, nuclear run-on assays showed that the rate of transcription of the utrophin gene was nearly identical between EDL and soleus muscles, indicating that increased mRNA stability accounts for the higher levels of utrophin in slow muscles. Direct plasmid injections of reporter gene constructs showed that cis-acting elements contained within the utrophin 3′-untranslated region (3′-UTR) confer greater stability to chimeric LacZ transcripts in soleus muscles. Finally, we observed a clear difference between EDL and soleus muscles in the abundance of RNA-binding proteins interacting with the utrophin 3′-UTR. Together, these findings highlight the contribution of posttranscriptional events in regulating the expression of utrophin in muscle.

scholarly journals POS-1 and GLD-1 repress glp-1 translation through a conserved binding-site cluster

2012 ◽  
Vol 23 (23) ◽  
pp. 4473-4483 ◽  
Author(s):  
Brian M. Farley ◽  
Sean P. Ryder
Keyword(s):  
Cell Fate ◽  
Binding Sites ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Regulatory Elements ◽  
Regulatory Sequence ◽  
Regulatory Pathways ◽  
Fate Specification

RNA-binding proteins (RBPs) coordinate cell fate specification and differentiation in a variety of systems. RNA regulation is critical during oocyte development and early embryogenesis, in which RBPs control expression from maternal mRNAs encoding key cell fate determinants. The Caenorhabditis elegans Notch homologue glp-1 coordinates germline progenitor cell proliferation and anterior fate specification in embryos. A network of sequence-specific RBPs is required to pattern GLP-1 translation. Here, we map the cis-regulatory elements that guide glp-1 regulation by the CCCH-type tandem zinc finger protein POS-1 and the STAR-domain protein GLD-1. Our results demonstrate that both proteins recognize the glp-1 3′ untranslated region (UTR) through adjacent, overlapping binding sites and that POS-1 binding excludes GLD-1 binding. Both factors are required to repress glp-1 translation in the embryo, suggesting that they function in parallel regulatory pathways. It is intriguing that two equivalent POS-1–binding sites are present in the glp-1 3′ UTR, but only one, which overlaps with a translational derepression element, is functional in vivo. We propose that POS-1 regulates glp-1 mRNA translation by blocking access of other RBPs to a key regulatory sequence.

scholarly journals Nuclear RNP complex assembly initiates cytoplasmic RNA localization

2004 ◽  
Vol 165 (2) ◽  
pp. 203-211 ◽  
Author(s):  
Tracy L. Kress ◽  
Young J. Yoon ◽  
Kimberly L. Mowry
Keyword(s):  
Protein Interactions ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Localization ◽  
Rna Sequences ◽  
Cytoplasmic Rna ◽  
Rnp Complex ◽  
Maternal Mrnas ◽  
Protein Components

Cytoplasmic localization of mRNAs is a widespread mechanism for generating cell polarity and can provide the basis for patterning during embryonic development. A prominent example of this is localization of maternal mRNAs in Xenopus oocytes, a process requiring recognition of essential RNA sequences by protein components of the localization machinery. However, it is not yet clear how and when such protein factors associate with localized RNAs to carry out RNA transport. To trace the RNA–protein interactions that mediate RNA localization, we analyzed RNP complexes from the nucleus and cytoplasm. We find that an early step in the localization pathway is recognition of localized RNAs by specific RNA-binding proteins in the nucleus. After transport into the cytoplasm, the RNP complex is remodeled and additional transport factors are recruited. These results suggest that cytoplasmic RNA localization initiates in the nucleus and that binding of specific RNA-binding proteins in the nucleus may act to target RNAs to their appropriate destinations in the cytoplasm.

scholarly journals The iron-responsive element (IRE)/iron-regulatory protein 1 (IRP1)–cytosolic aconitase iron-regulatory switch does not operate in plants

2007 ◽  
Vol 405 (3) ◽  
pp. 523-531 ◽  
Author(s):  
Nicolas Arnaud ◽  
Karl Ravet ◽  
Andrea Borlotti ◽  
Brigitte Touraine ◽  
Jossia Boucherez ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulatory Protein ◽  
Binding Activity ◽  
Loss Of Function ◽  
Structural Element ◽  
Iron Regulatory Proteins ◽  
Cis Acting ◽  
Model Plant Arabidopsis Thaliana ◽  
Responsive Element

Animal cytosolic ACO (aconitase) and bacteria ACO are able to switch to RNA-binding proteins [IRPs (iron-regulatory proteins)], thereby playing a key role in the regulation of iron homoeostasis. In the model plant Arabidopsis thaliana, we have identified three IRP1 homologues, named ACO1–3. To determine whether or not they may encode functional IRP proteins and regulate iron homoeostasis in plants, we have isolated loss-of-function mutants in the three genes. The aco1-1 and aco3-1 mutants show a clear decrease in cytosolic ACO activity. However, none of the mutants is affected in respect of the accumulation of the ferritin transcript or protein in response to iron excess. cis-acting elements potentially able to bind to the IRP have been searched for in silico in the Arabidopsis genome. They appear to be very rare sequences, found in the 5′-UTR (5′-untranslated region) or 3′-UTR of a few genes unrelated to iron metabolism. They are therefore unlikely to play a functional role in the regulation of iron homoeostasis. Taken together, our results demonstrate that, in plants, the cytosolic ACO is not converted into an IRP and does not regulate iron homoeostasis. In contrast with animals, the RNA binding activity of plant ACO, if any, would be more likely to be attributable to a structural element, rather than to a canonical sequence.

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