Статті в журналах: "MRNA fate"

1

Denti, Michela A., Gabriella Viero, Alessandro Provenzani, Alessandro Quattrone, and Paolo Macchi. "mRNA fate." RNA Biology 10, no. 3 (March 2013): 360–66. http://dx.doi.org/10.4161/rna.23770.

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2

Singh, Guramrit, and Zhongxia Yi. "Connections between mRNP Composition and mRNA Fate." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.00219.

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3

Wiederhold, Katrin, and Lori A. Passmore. "Cytoplasmic deadenylation: regulation of mRNA fate." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1531–36. http://dx.doi.org/10.1042/bst0381531.

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The poly(A) tail of mRNA has an important influence on the dynamics of gene expression. On one hand, it promotes enhanced mRNA stability to allow production of the protein, even after inactivation of transcription. On the other hand, shortening of the poly(A) tail (deadenylation) slows down translation of the mRNA, or prevents it entirely, by inducing mRNA decay. Thus deadenylation plays a crucial role in the post-transcriptional regulation of gene expression, deciding the fate of individual mRNAs. It acts both in basal mRNA turnover, as well as in temporally and spatially regulated translation and decay of specific mRNAs. In the present paper, we discuss mRNA deadenylation in eukaryotes, focusing on the main deadenylase, the Ccr4–Not complex, including its composition, regulation and functional roles.

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4

Zlotorynski, Eytan. "Promoters of mRNA fate." Nature Reviews Molecular Cell Biology 15, no. 9 (August 22, 2014): 563. http://dx.doi.org/10.1038/nrm3865.

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5

Kuhn, L. C. "The cytoplasmic fate of mRNA." Journal of Cell Science 114, no. 10 (May 15, 2001): 1797–98. http://dx.doi.org/10.1242/jcs.114.10.1797a.

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Translational Control of Gene Expression edited by N. Sonenberg, J. W. B. Hershey and M. B. Matthews Cold Spring Harbor Laboratory Press (2000) 1020 pages. ISBN 0–87969-568-4 US$115 At the beginning of the 90s most molecular biologists were focusing on transcription and RNA splicing. mRNA translation and its temporal and spatial regulation seemed research topics for insiders at that time. However, all aspects of mRNA fate in the cytoplasm will certainly attract much more attention during the next decade. The field is now flourishing with connections to all disciplines of biology. This book will help you to realize the tremendous variation of translational regulatory mechanisms existing in nature. The evidence for their importance has become so overwhelming that nobody seriously interested in gene expression can ignore it any longer. It is the great merit of the editors of this book that they have brought together an impressive series of first-class reviews written by the most prominent scientists in the field. The new monograph takes a fresh look at the field and is greatly expanded compared with the earlier 1996 version. The book is judiciously divided into two parts. The first part comprises eight broad chapters, giving an overview of the main principles of protein synthesis and its regulation. They serve as a thorough basis for the second part, which comprises twenty-eight chapters, each about 20 pages in length, that present in depth additional exciting areas in which there is strong research activity. Your appetite for this book will be stimulated right at the beginning by the wonderful introductory chapter, which is written jointly by the editors and defines the field in its entire complexity. Given that translation is of course a unifying principle of all living organisms, why are there such a large number of different control mechanisms modulating the use of mRNA templates and making actual protein level not predictable from RNA quantity alone? Are these just remnants of an RNA world or, as the authors seem to believe, effective adaptations for fine-tuning gene expression that have been opportunistically added during evolution? Five broad chapters are devoted to our knowledge of initiation, elongation and termination of translation both in eukaryotes and in prokaryotes. It is amazing how much detail has been added, in just the past five years, to our picture of the biochemistry, structure and function of ribosomes, initiation sites, and translation factors. However, translational control of gene expression is not just a matter of the translation machinery alone. It seems rather that the tremendously versatile mRNA sequences and structures impose the way they are seen by the translation apparatus and its factors. Particularly in eukaryotes, the untranslated parts of mRNAs play a decisive role by providing additional interaction sites for cytoplasmic proteins that modulate mRNA stability, mRNA localization or accessibility of mRNAs to translation. In turn, many of the proteins interacting with mRNA are themselves regulated by metabolites or post-translational modifications. This is beautifully documented in an exciting chapter on the role of translational control in developmental decisions. For example, in Drosophila, a specific cascade of factors acting on RNA localization and translation controls the anterior-posterior body axis. In C. elegans, the fate of germ-line cells is determined by translational repression. And you will find many more such examples. Another important section of the book is devoted to changes in translation that occur during virus infection. Again one is amazed by the variety of ways by which viruses divert the host translation apparatus for their own sake. The shorter chapters give insight into additional exciting areas in the field. For example, research into how heat shock or signal transduction pathways feed into translation, what we know about mRNA degradation of normal and nonsense-containing transcripts, and the evidence that local synaptic protein synthesis represents a molecular hallmark of learning and memory. This book is the most complete and up-to-date review of translational control mechanisms. It is a must for students entering the field, and it will constitute for many years a major reference guide for any investigator who is seriously interested in the full picture of gene expression.

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6

Li, Mo, Ignacio Sancho-Martinez, and Juan Belmonte. "Cell fate conversion by mRNA." Stem Cell Research & Therapy 2, no. 1 (2011): 5. http://dx.doi.org/10.1186/scrt46.

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7

H Beilharz, Traude, and Thomas Preiss. "?Cradle?to?grave? regulation of mRNA fate." Microbiology Australia 28, no. 2 (2007): 85. http://dx.doi.org/10.1071/ma07085.

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Microarray studies in Saccharomyces cerevisiae have set the benchmark for genome-wide analyses, available data-sets covering practically every stage of gene expression from DNA-binding by transcription factors to mRNA export, sub-cellular localisation, translation and decay. A theme to emerge from such data has been the prevalence of coordinate gene regulation. Thus, gene modules or ?regulons? are well recognised at the level of gene transcription and the activity of transcription factors provides an obvious molecular explanation for such coordination. More surprising was the organisation of mRNAs into co-regulated ?post-transcriptional operons?. RNA-binding proteins (RBPs), but also ribonucleoprotein (RNP) complexes involving noncoding RNA, have been proposed as the conceptual equivalent of transcription factors at this level.

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8

Ols, Sebastian, and Karin Loré. "Imaging the early fate of mRNA vaccines." Nature Biomedical Engineering 3, no. 5 (May 2019): 331–32. http://dx.doi.org/10.1038/s41551-019-0399-y.

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9

Forget, Amélie, and Pascal Chartrand. "Cotranscriptional assembly of mRNP complexes that determine the cytoplasmic fate of mRNA." Transcription 2, no. 2 (March 2011): 86–90. http://dx.doi.org/10.4161/trns.2.2.14857.

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10

Stöhr, Nadine, Marcell Lederer, Claudia Reinke, Sylke Meyer, Mechthild Hatzfeld, Robert H. Singer, and Stefan Hüttelmaier. "ZBP1 regulates mRNA stability during cellular stress." Journal of Cell Biology 175, no. 4 (November 13, 2006): 527–34. http://dx.doi.org/10.1083/jcb.200608071.

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An essential constituent of the integrated stress response (ISR) is a reversible translational suppression. This mRNA silencing occurs in distinct cytoplasmic foci called stress granules (SGs), which transiently associate with processing bodies (PBs), typically serving as mRNA decay centers. How mRNAs are protected from degradation in these structures remains elusive. We identify that Zipcode-binding protein 1 (ZBP1) regulates the cytoplasmic fate of specific mRNAs in nonstressed cells and is a key regulator of mRNA turnover during the ISR. ZBP1 association with target mRNAs in SGs was not essential for mRNA targeting to SGs. However, ZBP1 knockdown induced a selective destabilization of target mRNAs during the ISR, whereas forced expression increased mRNA stability. Our results indicate that although targeting of mRNAs to SGs is nonspecific, the stabilization of mRNAs during cellular stress requires specific protein–mRNA interactions. These retain mRNAs in SGs and prevent premature decay in PBs. Hence, mRNA-binding proteins are essential for translational adaptation during cellular stress by modulating mRNA turnover.

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11

Tudisca, V., C. Simpson, L. Castelli, J. Lui, N. Hoyle, S. Moreno, M. Ashe, and P. Portela. "PKA isoforms coordinate mRNA fate during nutrient starvation." Journal of Cell Science 125, no. 21 (August 16, 2012): 5221–32. http://dx.doi.org/10.1242/jcs.111534.

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12

Malim, M. H., and B. R. Cullen. "Rev and the fate of pre-mRNA in the nucleus: implications for the regulation of RNA processing in eukaryotes." Molecular and Cellular Biology 13, no. 10 (October 1993): 6180–89. http://dx.doi.org/10.1128/mcb.13.10.6180-6189.1993.

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Although a great deal is known about the regulation of gene expression in terms of transcription, relatively little is known about the modulation of pre-mRNA processing. In this study, we exploited a genetically regulated system, human immunodeficiency virus type 1 (HIV-1) and its trans-activator Rev, to examine events that occur between the synthesis of pre-mRNA in the nucleus and the translation of mRNA in the cytoplasm. Unlike the majority of eukaryotic pre-mRNAs whose introns are efficiently recognized and spliced prior to nucleocytoplasmic transport, HIV-1 mRNAs containing functional introns must be exported to the cytoplasm for the expression of many viral proteins. Using human T cells containing stably integrated proviruses, we demonstrate that such incompletely spliced viral mRNAs are exported to the cytoplasm only in the presence of the Rev trans-activator. In the absence of Rev, these intron-containing RNAs are sequestered in the T-cell nucleus and either spliced or, more commonly, degraded. Because Rev does not inhibit the expression of fully spliced viral mRNA species in T cells, we propose that Rev, rather than inhibiting viral pre-mRNA splicing, is acting here both to prevent the nuclear degradation of HIV-1 pre-mRNAs and to induce their translocation to the cytoplasm. Taken together, these findings indicate that the cellular factors responsible for the nuclear retention of unspliced pre-mRNAs, although most probably splicing factors, do not invariably commit these RNAs to productive splicing and can, instead, program such transcripts for degradation.

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13

Malim, M. H., and B. R. Cullen. "Rev and the fate of pre-mRNA in the nucleus: implications for the regulation of RNA processing in eukaryotes." Molecular and Cellular Biology 13, no. 10 (October 1993): 6180–89. http://dx.doi.org/10.1128/mcb.13.10.6180.

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Although a great deal is known about the regulation of gene expression in terms of transcription, relatively little is known about the modulation of pre-mRNA processing. In this study, we exploited a genetically regulated system, human immunodeficiency virus type 1 (HIV-1) and its trans-activator Rev, to examine events that occur between the synthesis of pre-mRNA in the nucleus and the translation of mRNA in the cytoplasm. Unlike the majority of eukaryotic pre-mRNAs whose introns are efficiently recognized and spliced prior to nucleocytoplasmic transport, HIV-1 mRNAs containing functional introns must be exported to the cytoplasm for the expression of many viral proteins. Using human T cells containing stably integrated proviruses, we demonstrate that such incompletely spliced viral mRNAs are exported to the cytoplasm only in the presence of the Rev trans-activator. In the absence of Rev, these intron-containing RNAs are sequestered in the T-cell nucleus and either spliced or, more commonly, degraded. Because Rev does not inhibit the expression of fully spliced viral mRNA species in T cells, we propose that Rev, rather than inhibiting viral pre-mRNA splicing, is acting here both to prevent the nuclear degradation of HIV-1 pre-mRNAs and to induce their translocation to the cytoplasm. Taken together, these findings indicate that the cellular factors responsible for the nuclear retention of unspliced pre-mRNAs, although most probably splicing factors, do not invariably commit these RNAs to productive splicing and can, instead, program such transcripts for degradation.

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14

Carroll, Johanna S., Sarah E. Munchel, and Karsten Weis. "The DExD/H box ATPase Dhh1 functions in translational repression, mRNA decay, and processing body dynamics." Journal of Cell Biology 194, no. 4 (August 15, 2011): 527–37. http://dx.doi.org/10.1083/jcb.201007151.

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Translation, storage, and degradation of messenger ribonucleic acids (mRNAs) are key steps in the posttranscriptional control of gene expression, but how mRNAs transit between these processes remains poorly understood. In this paper, we functionally characterized the DExD/H box adenosine triphosphatase (ATPase) Dhh1, a critical regulator of the cytoplasmic fate of mRNAs. Using mRNA tethering experiments in yeast, we showed that Dhh1 was sufficient to move an mRNA from an active state to translational repression. In actively dividing cells, translational repression was followed by mRNA decay; however, deleting components of the 5′–3′ decay pathway uncoupled these processes. Whereas Dhh1’s ATPase activity was not required to induce translational inhibition and mRNA decay when directly tethered to an mRNA, ATP hydrolysis regulated processing body dynamics and the release of Dhh1 from these RNA–protein granules. Our results place Dhh1 at the interface of translation and decay controlling whether an mRNA is translated, stored, or decayed.

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15

Terasaka, Tomohiro, Taeshin Kim, Hiral Dave, Bhakti Gangapurkar, Dequina A. Nicholas, Oscar Muñoz, Eri Terasaka, Danmei Li, and Mark A. Lawson. "The RNA-Binding Protein ELAVL1 Regulates GnRH Receptor Expression and the Response to GnRH." Endocrinology 160, no. 8 (June 12, 2019): 1999–2014. http://dx.doi.org/10.1210/en.2019-00203.

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Abstract Gonadotropin secretion, which is elicited by GnRH stimulation of the anterior pituitary gonadotropes, is a critical feature of reproductive control and the maintenance of fertility. In addition, activation of the GnRH receptor (GnRHR) regulates transcription and translation of multiple factors that regulate the signaling response and synthesis of gonadotropins. GnRH stimulation results in a broad redistribution of mRNA between active and inactive polyribosomes within the cell, but the mechanism of redistribution is not known. The RNA-binding protein embryonic lethal, abnormal vision, Drosophila-like 1 (ELAVL1) binds to AU-rich elements in mRNA and is one of the most abundant mRNA-binding proteins in eukaryotic cells. It is known to serve as a core component of RNA-binding complexes that direct the fate of mRNA. In LβT2 gonadotropes, we showed that ELAVL1 binds to multiple mRNAs encoding factors that are crucial for gonadotropin synthesis and release. Association with some mRNAs is GnRH sensitive but does not correlate with abundance of binding. We also showed MAPK-dependent changes in intracellular localization of ELAVL1 in response to GnRH stimulation. Knockdown of ELAVL1 gene expression resulted in reduced Lhb and Gnrhr mRNA levels, reduced cell surface expression of GnRHR, and reduced LH secretion in response to GnRH stimulation. Overall, these observations not only support the role of ELAVL1 in GnRHR-mediated regulation of gene expression and LH secretion but also indicate that other factors may contribute to the precise fate of mRNA in response to GnRH stimulation of gonadotropes.

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16

Jiao, Yan, Colin E. Bishop, and Baisong Lu. "Mex3c regulates insulin-like growth factor 1 (IGF1) expression and promotes postnatal growth." Molecular Biology of the Cell 23, no. 8 (April 15, 2012): 1404–13. http://dx.doi.org/10.1091/mbc.e11-11-0960.

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Insulin-like growth factor 1 (IGF1) mediates the growth-promoting activities of growth hormone. How Igf1 expression is regulated posttranscriptionally is unclear. Caenorhabditis elegans muscle excess 3 (MEX-3) is involved in cell fate specification during early embryonic development through regulating mRNAs involved in specifying cell fate. The function of its mammalian homologue, MEX3C, is unknown. Here we show that MEX3C deficiency in Mex3c homozygous mutant mice causes postnatal growth retardation and background-dependent perinatal lethality. Hypertrophy of chondrocytes in growth plates is significantly impaired. Circulating and bone local production of IGF1 are both decreased in mutant mice. Mex3c mRNA is strongly expressed in the testis and the brain, and highly expressed in resting and proliferating chondrocytes of the growth plates. MEX3C is able to enrich multiple mRNA species from tissue lysates, including Igf1. Igf1 expression in bone is decreased at the protein level but not at the mRNA level, indicating translational/posttranslational regulation. We propose that MEX3C protein plays an important role in enhancing the translation of Igf1 mRNA, which explains the perinatal lethality and growth retardation observed in MEX3C-deficient mice.

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17

Galloway, Alison, and Victoria H. Cowling. "mRNA cap regulation in mammalian cell function and fate." Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 1862, no. 3 (March 2019): 270–79. http://dx.doi.org/10.1016/j.bbagrm.2018.09.011.

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18

Höpfler, Markus, and Ramanujan S. Hegde. "Control of mRNA fate by its encoded nascent polypeptide." Molecular Cell 83, no. 16 (August 2023): 2840–55. http://dx.doi.org/10.1016/j.molcel.2023.07.014.

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19

Forbes Beadle, Lauren, Jennifer C. Love, Yuliya Shapovalova, Artem Artemev, Magnus Rattray, and Hilary L. Ashe. "Combined modelling of mRNA decay dynamics and single-molecule imaging in the Drosophila embryo uncovers a role for P-bodies in 5′ to 3′ degradation." PLOS Biology 21, no. 1 (January 17, 2023): e3001956. http://dx.doi.org/10.1371/journal.pbio.3001956.

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Regulation of mRNA degradation is critical for a diverse array of cellular processes and developmental cell fate decisions. Many methods for determining mRNA half-lives rely on transcriptional inhibition or metabolic labelling. Here, we use a non-invasive method for estimating half-lives for hundreds of mRNAs in the early Drosophila embryo. This approach uses the intronic and exonic reads from a total RNA-seq time series and Gaussian process regression to model the dynamics of premature and mature mRNAs. We show how regulation of mRNA stability is used to establish a range of mature mRNA dynamics during embryogenesis, despite shared transcription profiles. Using single-molecule imaging, we provide evidence that, for the mRNAs tested, there is a correlation between short half-life and mRNA association with P-bodies. Moreover, we detect an enrichment of mRNA 3′ ends in P-bodies in the early embryo, consistent with 5′ to 3′ degradation occurring in P-bodies for at least a subset of mRNAs. We discuss our findings in relation to recently published data suggesting that the primary function of P-bodies in other biological contexts is mRNA storage.

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20

Abbadi, Dounia, Ming Yang, Devon M. Chenette, John J. Andrews, and Robert J. Schneider. "Muscle development and regeneration controlled by AUF1-mediated stage-specific degradation of fate-determining checkpoint mRNAs." Proceedings of the National Academy of Sciences 116, no. 23 (May 21, 2019): 11285–90. http://dx.doi.org/10.1073/pnas.1901165116.

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AUF1 promotes rapid decay of mRNAs containing 3′ untranslated region (3′UTR) AU-rich elements (AREs). AUF1 depletion in mice accelerates muscle loss and causes limb girdle muscular dystrophy. Here, we demonstrate that the selective, targeted degradation by AUF1 of key muscle stem cell fate-determining checkpoint mRNAs regulates each stage of muscle development and regeneration by reprogramming each myogenic stage. Skeletal muscle stem (satellite) cell explants show that Auf1 transcription is activated with satellite cell activation by stem cell regulatory factor CTCF. AUF1 then targets checkpoint ARE-mRNAs for degradation, progressively reprogramming the transcriptome through each stage of myogenesis. Transition steps in myogenesis, from stem cell proliferation to differentiation to muscle fiber development, are each controlled by fate-determining checkpoint mRNAs, which, surprisingly, were found to be controlled in their expression by AUF1-targeted mRNA decay. Checkpoint mRNAs targeted by AUF1 include Twist1, decay of which promotes myoblast development; CyclinD1, decay of which blocks myoblast proliferation and initiates differentiation; and RGS5, decay of which activates Sonic Hedgehog (SHH) pathway-mediated differentiation of mature myotubes. AUF1 therefore orchestrates muscle stem cell proliferation, self-renewal, myoblast differentiation, and ultimately formation of muscle fibers through targeted, staged mRNA decay.

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21

Kim, Hyun-Jung. "Cell Fate Control by Translation: mRNA Translation Initiation as a Therapeutic Target for Cancer Development and Stem Cell Fate Control." Biomolecules 9, no. 11 (October 29, 2019): 665. http://dx.doi.org/10.3390/biom9110665.

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Translation of mRNA is an important process that controls cell behavior and gene regulation because proteins are the functional molecules that determine cell types and function. Cancer develops as a result of genetic mutations, which lead to the production of abnormal proteins and the dysregulation of translation, which in turn, leads to aberrant protein synthesis. In addition, the machinery that is involved in protein synthesis plays critical roles in stem cell fate determination. In the current review, recent advances in the understanding of translational control, especially translational initiation in cancer development and stem cell fate control, are described. Therapeutic targets of mRNA translation such as eIF4E, 4EBP, and eIF2, for cancer treatment or stem cell fate regulation are reviewed. Upstream signaling pathways that regulate and affect translation initiation were introduced. It is important to regulate the expression of protein for normal cell behavior and development. mRNA translation initiation is a key step to regulate protein synthesis, therefore, identifying and targeting molecules that are critical for protein synthesis is necessary and beneficial to develop cancer therapeutics and stem cells fate regulation.

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22

Quesenberry, Peter J. "Cell Fate Modulation by Microvesicles: Transcriptionally-Mediated and Long Term in Nature." Blood 118, no. 21 (November 18, 2011): 4801. http://dx.doi.org/10.1182/blood.v118.21.4801.4801.

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Abstract Abstract 4801 Cell-derived membrane enclosed vesicles containing mRNA, protein, microRNA, and DNA, can enter cells and effect a phenotype change. We have shown that lung-derived microvesicles enter marrow cells inducing them to express pulmonary epithelial cell-specific protein and mRNA, a variety of microRNA and to enhance their capacity to engraft in irradiated mice and express the phenotype of type II pneumocytes (Aliotta et al, Exp Hematol 38,2010). In the present studies using rat/mouse hybrid cultures and measuring species-specific mRNA, we have shown that immediately after co-culture of rat lung across from mouse marrow, mouse marrow cells express both rat and mouse specific surfactants B and C mRNA. However, when these cells are cultured in steel factor supported long-term culture, rat-specific mRNA disappears rapidly, while mouse-specific mRNA persists out to 12 weeks in liquid culture. Identical studies with rat liver cultured across from mouse marrow have shown early expression in mouse marrow of both rat and mouse albumin mRNA, but in long term in vitro culture, expression of albumin mRNA was mouse-specific. Thus, the major long-term persistent event is an alteration of transcription in the target marrow cells. In a similar fashion, marrow modulated by lung microvesicles in vitro and engrafted into lethally irradiated (950 cGy split dose) mice, evidences expression of pulmonary epithelial cell-specific mRNA or protein (surfactants) in host lung, marrow, thymus, spleen and liver 6 weeks after engraftment – the furthest time tested. These results indicate that microvesicle cell fate modulation is biologically meaningful and represents an important new mechanism for cell phenotype determination. Disclosures: No relevant conflicts of interest to declare.

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23

Mukherjee, Joyita, Orit Hermesh, Carolina Eliscovich, Nicolas Nalpas, Mirita Franz-Wachtel, Boris Maček та Ralf-Peter Jansen. "β-Actin mRNA interactome mapping by proximity biotinylation". Proceedings of the National Academy of Sciences 116, № 26 (12 червня 2019): 12863–72. http://dx.doi.org/10.1073/pnas.1820737116.

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The molecular function and fate of mRNAs are controlled by RNA-binding proteins (RBPs). Identification of the interacting proteome of a specific mRNA in vivo remains very challenging, however. Based on the widely used technique of RNA tagging with MS2 aptamers for RNA visualization, we developed a RNA proximity biotinylation (RNA-BioID) technique by tethering biotin ligase (BirA*) via MS2 coat protein at the 3′ UTR of endogenous MS2-tagged β-actin mRNA in mouse embryonic fibroblasts. We demonstrate the dynamics of the β-actin mRNA interactome by characterizing its changes on serum-induced localization of the mRNA. Apart from the previously known interactors, we identified more than 60 additional β-actin–associated RBPs by RNA-BioID. Among these, the KH domain-containing protein FUBP3/MARTA2 has been shown to be required for β-actin mRNA localization. We found that FUBP3 binds to the 3′ UTR of β-actin mRNA and is essential for β-actin mRNA localization, but does not interact with the characterized β-actin zipcode element. RNA-BioID provides a tool for identifying new mRNA interactors and studying the dynamic view of the interacting proteome of endogenous mRNAs in space and time.

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24

Gaillard, Hélène, and Andrés Aguilera. "A Novel Class of mRNA-containing Cytoplasmic Granules Are Produced in Response to UV-Irradiation." Molecular Biology of the Cell 19, no. 11 (November 2008): 4980–92. http://dx.doi.org/10.1091/mbc.e08-02-0193.

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Nucleic acids are substrates for different types of damage, but little is known about the fate of damaged RNAs. We addressed the existence of an RNA-damage response in yeast. The decay kinetics of GAL1p-driven mRNAs revealed a dose-dependent mRNA stabilization upon UV-irradiation that was not observed after heat or saline shocks, or during nitrogen starvation. UV-induced mRNA stabilization did not depend on DNA repair, damage checkpoint or mRNA degradation machineries. Notably, fluorescent in situ hybridization revealed that after UV-irradiation, polyadenylated mRNA accumulated in cytoplasmic foci that increased in size with time. In situ colocalization showed that these foci are not processing-bodies, eIF4E-, eIF4G-, and Pab1-containing bodies, stress granules, autophagy vesicles, or part of the secretory or endocytic pathways. These results point to the existence of a specific eukaryotic RNA-damage response, which leads to new polyadenylated mRNA-containing granules (UV-induced mRNA granules; UVGs). We propose that potentially damaged mRNAs, which may be deleterious to the cell, are temporarily stored in UVG granules to safeguard cell viability.

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25

Higashino, Fumihiro, Mariko Aoyagi, Akiko Takahashi, Masaho Ishino, Masato Taoka, Toshiaki Isobe, Masanobu Kobayashi, Yasunori Totsuka, Takao Kohgo, and Masanobu Shindoh. "Adenovirus E4orf6 targets pp32/LANP to control the fate of ARE-containing mRNAs by perturbing the CRM1-dependent mechanism." Journal of Cell Biology 170, no. 1 (June 27, 2005): 15–20. http://dx.doi.org/10.1083/jcb.200405112.

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E4orf6 plays an important role in the transportation of cellular and viral mRNAs and is known as an oncogene product of adenovirus. Here, we show that E4orf6 interacts with pp32/leucine-rich acidic nuclear protein (LANP). E4orf6 exports pp32/LANP from the nucleus to the cytoplasm with its binding partner, HuR, which binds to an AU-rich element (ARE) present within many protooncogene and cytokine mRNAs. We found that ARE-mRNAs, such as c-fos, c-myc, and cyclooxygenase-2, were also exported to and stabilized in the cytoplasm of E4orf6-expressing cells. The oncodomain of E4orf6 was necessary for both binding to pp32/LANP and effect for ARE-mRNA. C-fos mRNA was exported together with E4orf6, E1B-55kD, pp32/LANP, and HuR proteins. Moreover, inhibition of the CRM1-dependent export pathway failed to block the export of ARE-mRNAs mediated by E4orf6. Thus, E4orf6 interacts with pp32/LANP to modulate the fate of ARE-mRNAs by altering the CRM1-dependent export pathway.

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26

Parbin, Sabnam, Subha Damodharan, and Purusharth I. Rajyaguru. "Arginine methylation and cytoplasmic mRNA fate: An exciting new partnership." Yeast 38, no. 8 (June 7, 2021): 441–52. http://dx.doi.org/10.1002/yea.3653.

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27

Guo, Minjun, Xinhui Liu, Xiaotong Zheng, Yinghui Huang, and Xuechai Chen. "m6A RNA Modification Determines Cell Fate by Regulating mRNA Degradation." Cellular Reprogramming 19, no. 4 (August 2017): 225–31. http://dx.doi.org/10.1089/cell.2016.0041.

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28

Enssle, J., W. Kugler, M. W. Hentze, and A. E. Kulozik. "Determination of mRNA fate by different RNA polymerase II promoters." Proceedings of the National Academy of Sciences 90, no. 21 (November 1, 1993): 10091–95. http://dx.doi.org/10.1073/pnas.90.21.10091.

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29

Woodward, Lauren A., Justin W. Mabin, Pooja Gangras, and Guramrit Singh. "The exon junction complex: a lifelong guardian of mRNA fate." Wiley Interdisciplinary Reviews: RNA 8, no. 3 (December 23, 2016): e1411. http://dx.doi.org/10.1002/wrna.1411.

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30

McKee, Adrienne E., and Pamela A. Silver. "REF-ereeing the Cytoplasmic Fate of mRNA via Nuclear Export." Developmental Cell 6, no. 6 (June 2004): 740–42. http://dx.doi.org/10.1016/j.devcel.2004.05.014.

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31

Hoyle, Nathaniel P., Lydia M. Castelli, Susan G. Campbell, Leah E. A. Holmes, and Mark P. Ashe. "Stress-dependent relocalization of translationally primed mRNPs to cytoplasmic granules that are kinetically and spatially distinct from P-bodies." Journal of Cell Biology 179, no. 1 (October 1, 2007): 65–74. http://dx.doi.org/10.1083/jcb.200707010.

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Cytoplasmic RNA granules serve key functions in the control of messenger RNA (mRNA) fate in eukaryotic cells. For instance, in yeast, severe stress induces mRNA relocalization to sites of degradation or storage called processing bodies (P-bodies). In this study, we show that the translation repression associated with glucose starvation causes the key translational mediators of mRNA recognition, eIF4E, eIF4G, and Pab1p, to resediment away from ribosomal fractions. These mediators then accumulate in P-bodies and in previously unrecognized cytoplasmic bodies, which we define as EGP-bodies. Our kinetic studies highlight the fundamental difference between EGP- and P-bodies and reflect the complex dynamics surrounding reconfiguration of the mRNA pool under stress conditions. An absence of key mRNA decay factors from EGP-bodies points toward an mRNA storage function for these bodies. Overall, this study highlights new potential control points in both the regulation of mRNA fate and the global control of translation initiation.

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32

Reznik, Boris, and Jens Lykke-Andersen. "Regulated and quality-control mRNA turnover pathways in eukaryotes." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1506–10. http://dx.doi.org/10.1042/bst0381506.

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Gene expression can be regulated at multiple levels, including transcription, RNA processing, RNA localization, translation and, finally, RNA turnover. RNA degradation may occur at points along the processing pathway or during translation as it undergoes quality control by RNA surveillance systems. Alternatively, mRNAs may be subject to regulated degradation, often mediated by cis-encoded determinants in the mRNA sequence that, through the recruitment of trans factors, determine the fate of the mRNA. The aim of the present review is to highlight mechanisms of regulated and quality-control RNA degradation in eukaryotic cells, with an emphasis on mammals.

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Bronson, Katherine, Meenakshisundaram Balasubramaniam, Linda Hardy, Gwen V. Childs, Melanie C. MacNicol, and Angus M. MacNicol. "The Cell Fate Determinant Musashi Is Controlled Through Dynamic Protein:Protein Interactions." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A555. http://dx.doi.org/10.1210/jendso/bvab048.1131.

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Abstract The Musashi RNA-binding protein functions as a gatekeeper of cell maturation and plasticity through the control of target mRNA translation. It is understood that Musashi promotes stem cell self-renewal and opposes differentiation. While Musashi is best characterized as a repressor of target mRNA translation, we have shown that Musashi can activate target mRNA translation in a cell context specific manner via regulatory phosphorylation on two evolutionarily conserved C-terminal serine residues. Our recent work has found that Musashi is expressed in pituitary stem cells as well as in differentiated hormone producing cell lineages in the adult pituitary. We hypothesize that Musashi maintains cell fate plasticity in the adult pituitary to allow the gland to modulate hormone production in response to changing organismal needs. Here, we seek to understand the regulation of Musashi function. Both Musashi isoforms (Musashi1 and Musashi2) contain two RNA-recognition motifs (RRMs) that bind to specific sequences in the 3’-UTR of target mRNA transcripts; however, neither isoform has enzymatic properties and thus functions through interactions with other proteins to regulate translational outcomes, but the identity and role of Musashi partner proteins is largely unknown. In this study, we have identified co-associated partner proteins that functionally contribute to Musashi-dependent mRNA translational activation during the maturation of Xenopus oocytes. Using mass spectrometry, we identified 29 co-associated proteins that interact specifically with Musashi1 during oocyte maturation and determined that the Musashi co-associated proteins ePABP, PABP4, LSM14A/B, CELF2, PUM1, ELAV1, ELAV2, and DDX6 attenuated oocyte maturation through individual antisense DNA oligo knockdowns. An assessment of the role of these cofactors in the control of Musashi-dependent target mRNA translation is in progress. In addition to studying co-associated proteins, we have created a computational 3D model of the Musashi1 molecule to assist in our investigation Musashi dimerization. This model has indicated that both Musashi1 dimerization and Musashi1:Musashi2 heterodimerization are energetically favorable, and co-pulldown studies have verified both Musashi1 homo-dimerization and Musashi1:Musashi2 heterodimerization in vivo. Computational modeling of Musashi dimer complexes has also identified the key amino acids necessary for these interactions. The contribution of each co-associated protein’s influence on Musashi-dependent translation, relative to the requirement for Musashi:Musashi dimerization, is expected to provide unparalleled insight into regulation of Musashi action. Moreover, cell type specific regulation of association of Musashi co-factors would directly influence Musashi target mRNA translation in oocyte maturation and during pituitary cell plasticity.

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Xu, N., C. Y. Chen, and A. B. Shyu. "Modulation of the fate of cytoplasmic mRNA by AU-rich elements: key sequence features controlling mRNA deadenylation and decay." Molecular and Cellular Biology 17, no. 8 (August 1997): 4611–21. http://dx.doi.org/10.1128/mcb.17.8.4611.

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Regulation of cytoplasmic deadenylation has a direct impact on the fate of mRNA and, consequently, its expression in the cytoplasm. AU-rich elements (AREs) found in the 3' untranslated regions of many labile mRNAs are the most common RNA-destabilizing elements known in mammalian cells. AREs direct accelerated deadenylation as the first step in mRNA turnover. Recently we have proposed that AREs can be divided into three different classes. mRNAs bearing either the class I AUUUA-containing ARE or the class III non-AUUUA ARE display synchronous poly(A) shortening, whereas class II ARE-containing mRNAs are deadenylated asynchronously, with the formation of poly(A)- intermediates. In this study, we have systematically characterized the deadenylation kinetics displayed by various AREs and their mutant derivatives. We find that a cluster of five or six copies of AUUUA motifs in close proximity forming various degrees of reiteration is the key feature that dictates the choice between processive versus distributive deadenylation. An AU-rich region 20 to 30 nucleotides long immediately 5' to this cluster of AUUUA motifs can greatly enhance the destabilizing ability of the AUUUA cluster and is, therefore, an integral part of the class I and class II AREs. These two features are the defining characteristics of class II AREs. Our results are consistent with the interpretation that the pentanucleotide AUUUA, rather than the nonamer UUAUUUA(U/A)(U/A), is both an essential and the minimal sequence motif of AREs. Our study provides the groundwork for future characterization of ARE-binding proteins identified by in vitro gel shift assays in order to stringently define their potential role in the ARE-mediated decay pathway. Moreover, transformation of deadenylation kinetics from one type to the other by mutations of AREs implies the existence of cross talk between the ARE and 3' poly(A) tail, which dictates the decay kinetics.

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35

Holmes, L. E. A., S. G. Campbell, S. K. De Long, A. B. Sachs, and M. P. Ashe. "Loss of Translational Control in Yeast Compromised for the Major mRNA Decay Pathway." Molecular and Cellular Biology 24, no. 7 (April 1, 2004): 2998–3010. http://dx.doi.org/10.1128/mcb.24.7.2998-3010.2004.

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ABSTRACT The cytoplasmic fate of mRNAs is dictated by the relative activities of the intimately connected mRNA decay and translation initiation pathways. In this study, we have found that yeast strains compromised for stages downstream of deadenylation in the major mRNA decay pathway are incapable of inhibiting global translation initiation in response to stress. In the past, the paradigm of the eIF2α kinase-dependent amino acid starvation pathway in yeast has been used to evaluate this highly conserved stress response in all eukaryotic cells. Using a similar approach we have found that even though the mRNA decay mutants maintain high levels of general translation, they exhibit many of the hallmarks of amino acid starvation, including increased eIF2α phosphorylation and activated GCN4 mRNA translation. Therefore, these mutants appear translationally oblivious to decreased ternary complex abundance, and we propose that this is due to higher rates of mRNA recruitment to the 40S ribosomal subunit.

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36

Barr, Justinn, Rudolf Gilmutdinov, Linus Wang, Yulii Shidlovskii, and Paul Schedl. "The Drosophila CPEB Protein Orb Specifies Oocyte Fate by a 3′UTR-Dependent Autoregulatory Loop." Genetics 213, no. 4 (October 8, 2019): 1431–46. http://dx.doi.org/10.1534/genetics.119.302687.

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orb encodes one of the two fly CPEB proteins. These widely conserved proteins bind to the 3′UTRs of target messenger RNAs (mRNAs) and activate or repress their translation. We show here that a positive autoregulatory loop driven by the orb gene propels the specification of oocyte identity in Drosophila egg chambers. Oocyte fate specification is mediated by a 3′UTR-dependent mechanism that concentrates orb mRNAs and proteins in one of the two pro-oocytes in the 16-cell germline cyst. When the orb 3′UTR is deleted, orb mRNA and protein fail to localize and all 16 cells become nurse cells. In wild type, the oocyte is specified when orb and other gene products concentrate in a single cell in region 2b of the germarium. A partially functional orb 3′UTR replacement delays oocyte specification until the egg chambers reach stage 2 of oogenesis. Before this point, orb mRNA and protein are unlocalized, as are other markers of oocyte identity, and the oocyte is not specified. After stage 2, ∼50% of the chambers successfully localize orb in a single cell, and this cell assumes oocyte identity. In the remaining chambers, the orb autoregulatory loop is not activated and no oocyte is formed. Finally, maintenance of oocyte identity requires continuous orb activity.

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37

Banik*, Jewel, Juchan Lim*, Hardy L. Linda, Angela Katherine Odle, Gwen V. Childs, Melanie C. MacNicol, and Angus M. MacNicol. "The Musashi1 RNA-Binding Protein Functions as a Leptin-Regulated Enforcer of Pituitary Cell Fate and Hormone Production." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A654. http://dx.doi.org/10.1210/jendso/bvab048.1333.

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Abstract The pituitary gland is the major endocrine organ that produces and secretes hormones in response to hypothalamic signals to regulate important processes like growth, reproduction, and stress. The anterior pituitary adapts to metabolic and reproductive needs by exhibiting cellular plasticity, resulting in altered hormone production and secretion. The adipokine, leptin, serves a critical role to couple energy status to pituitary function. We have recently reported that the cell fate determinant, Musashi, functions as a post-transcriptional regulator of target mRNA translation in the mouse pituitary and have speculated that Musashi may modulate pituitary cell plasticity. However, the underlying mechanisms governing such pituitary plasticity are not fully understood. Musashi is an mRNA binding protein that is required for self-renewal, proliferation, and to control the differentiation of stem and progenitor cells. We have recently shown that Musashi is expressed in Sox2+ pituitary stem cells and surprisingly, we also found Musashi expression in all differentiated hormone expressing cell lineages in the adult anterior pituitary. The role of Musashi in these mature differentiated cells is unknown. We have observed that a range of critical pituitary mRNAs, including the lineage specification transcription factors Prop1 and Pou1f1, as well as hormone mRNAs including Tshb, Prl, and Gnrhr, all contain consensus Musashi binding elements (MBEs) in their 3’ untranslated regions (3’ UTRs). Using RNA electrophoretic mobility shift assays (EMSAs) and luciferase mRNA translation reporter assays we show that Musashi binds to these mRNAs and exerts inhibitory control of mRNA translation. Moreover, we determined that leptin stimulation opposes the ability of Musashi to exert translational repression of the Pou1f1 and Gnrhr 3’ UTRs. This de-repression does not require regulatory phosphorylation of Musashi on two conserved C-terminal serine residues. Interestingly in the same cell assay system, Musashi exerts translational activation of the Prop1 3’ UTR. We observed that this translational activation requires Musashi phosphorylation on the two regulatory C-terminal serine residues, consistent with the requirement for regulatory phosphorylation to drive translational activation of Musashi target mRNAs during Xenopus oocyte cell maturation. The distinction between MBEs in 3’ UTRs that exert repression (Pou1f1, Prl, Tshb, and Gnrhr) and the Prop1 3’ UTR that directs translational activation is under investigation. We propose that Musashi acts as a bifunctional regulator of pituitary hormone production and lineage specification and may function to maintain pituitary hormone plasticity in response to changing organismal needs.

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38

Hoernes, Thomas Philipp, David Heimdörfer, Daniel Köstner, Klaus Faserl, Felix Nußbaumer, Raphael Plangger, Christoph Kreutz, Herbert Lindner, and Matthias David Erlacher. "Eukaryotic Translation Elongation is Modulated by Single Natural Nucleotide Derivatives in the Coding Sequences of mRNAs." Genes 10, no. 2 (January 25, 2019): 84. http://dx.doi.org/10.3390/genes10020084.

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RNA modifications are crucial factors for efficient protein synthesis. All classes of RNAs that are involved in translation are modified to different extents. Recently, mRNA modifications and their impact on gene regulation became a focus of interest because they can exert a variety of effects on the fate of mRNAs. mRNA modifications within coding sequences can either directly or indirectly interfere with protein synthesis. In order to investigate the roles of various natural occurring modified nucleotides, we site-specifically introduced them into the coding sequence of reporter mRNAs and subsequently translated them in HEK293T cells. The analysis of the respective protein products revealed a strong position-dependent impact of RNA modifications on translation efficiency and accuracy. Whereas a single 5-methylcytosine (m5C) or pseudouridine () did not reduce product yields, N1-methyladenosine (m1A) generally impeded the translation of the respective modified mRNA. An inhibitory effect of 2′O-methlyated nucleotides (Nm) and N6-methyladenosine (m6A) was strongly dependent on their position within the codon. Finally, we could not attribute any miscoding potential to the set of mRNA modifications tested in HEK293T cells.

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39

Meijer, Hedda A., Tobias Schmidt, Sarah L. Gillen, Claudia Langlais, Rebekah Jukes-Jones, Cornelia H. de Moor, Kelvin Cain, Ania Wilczynska, and Martin Bushell. "DEAD-box helicase eIF4A2 inhibits CNOT7 deadenylation activity." Nucleic Acids Research 47, no. 15 (June 10, 2019): 8224–38. http://dx.doi.org/10.1093/nar/gkz509.

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Abstract The CCR4–NOT complex plays an important role in the translational repression and deadenylation of mRNAs. However, little is known about the specific roles of interacting factors. We demonstrate that the DEAD-box helicases eIF4A2 and DDX6 interact directly with the MA3 and MIF domains of CNOT1 and compete for binding. Furthermore, we now show that incorporation of eIF4A2 into the CCR4–NOT complex inhibits CNOT7 deadenylation activity in contrast to DDX6 which enhances CNOT7 activity. Polyadenylation tests (PAT) on endogenous mRNAs determined that eIF4A2 bound mRNAs have longer poly(A) tails than DDX6 bound mRNAs. Immunoprecipitation experiments show that eIF4A2 does not inhibit CNOT7 association with the CCR4–NOT complex but instead inhibits CNOT7 activity. We identified a CCR4–NOT interacting factor, TAB182, that modulates helicase recruitment into the CCR4–NOT complex, potentially affecting the outcome for the targeted mRNA. Together, these data show that the fate of an mRNA is dependent on the specific recruitment of either eIF4A2 or DDX6 to the CCR4–NOT complex which results in different pathways for translational repression and mRNA deadenylation.

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40

Mohanan, Gayatri, Amiyaranjan Das, and Purusharth I. Rajyaguru. "Genotoxic stress response: What is the role of cytoplasmic mRNA fate?" BioEssays 43, no. 8 (June 7, 2021): 2000311. http://dx.doi.org/10.1002/bies.202000311.

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41

Perry, Noam, Marina Volin, and Hila Toledano. "microRNAs in Drosophila regulate cell fate by repressing single mRNA targets." International Journal of Developmental Biology 61, no. 3-4-5 (2017): 165–70. http://dx.doi.org/10.1387/ijdb.160271ht.

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42

Steiger, Michelle A., and Carolyn J. Decker. "New Twists in Understanding the Fate of Antisense Oligodeoxynucleotide mRNA Targets." Molecular Cell 8, no. 4 (October 2001): 732–33. http://dx.doi.org/10.1016/s1097-2765(01)00370-7.

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43

Klausner, Richard D., Tracey A. Rouault, and Joe B. Harford. "Regulating the fate of mRNA: The control of cellular iron metabolism." Cell 72, no. 1 (January 1993): 19–28. http://dx.doi.org/10.1016/0092-8674(93)90046-s.

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44

Gonsalvez, G. B., T. K. Rajendra, Y. Wen, K. Praveen, and A. G. Matera. "Sm proteins specify germ cell fate by facilitating oskar mRNA localization." Development 137, no. 14 (June 22, 2010): 2341–51. http://dx.doi.org/10.1242/dev.042721.

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45

Redder, Peter. "How does sub-cellular localization affect the fate of bacterial mRNA?" Current Genetics 62, no. 4 (March 14, 2016): 687–90. http://dx.doi.org/10.1007/s00294-016-0587-1.

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46

Breedon, Sarah A., and Kenneth B. Storey. "Lost in Translation: Exploring microRNA Biogenesis and Messenger RNA Fate in Anoxia-Tolerant Turtles." Oxygen 2, no. 2 (June 17, 2022): 227–45. http://dx.doi.org/10.3390/oxygen2020017.

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Red-eared slider turtles face natural changes in oxygen availability throughout the year. This includes long-term anoxic brumation where they reduce their metabolic rate by ~90% for months at a time, which they survive without apparent tissue damage. This metabolic rate depression (MRD) is underlaid by various regulatory mechanisms, including messenger RNA (mRNA) silencing via microRNA (miRNA), leading to mRNA decay or translational inhibition in processing bodies (P-bodies) and stress granules. Regulation of miRNA biogenesis was assessed in red-eared slider turtle liver and skeletal muscle via immunoblotting. Hepatic miRNA biogenesis was downregulated in early processing steps, while later steps were upregulated. These contradictory findings indicate either overall decreased miRNA biogenesis, or increased biogenesis if sufficient pre-miRNA stores were produced in early anoxia. Conversely, muscle showed clear upregulation of multiple biogenesis steps indicating increased miRNA production. Additionally, immunoblotting indicated that P-bodies may be favoured by the liver for mRNA storage/decay during reoxygenation with a strong suppression of stress granule proteins in anoxia and reoxygenation. Muscle however showed downregulation of P-bodies during anoxia and reoxygenation, and upregulation of stress granules for mRNA storage during reoxygenation. This study advances our understanding of how these champion anaerobes regulate miRNA biogenesis to alter miRNA expression and mRNA fate during prolonged anoxia.

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47

Yip, Victor, Gillie Roth, Elizabeth Torres, Sara Wichner, Craig Blanchette, Amrita Kamath, and Ben-Quan Shen. "Abstract LB242: Characterizing the fate<tissue distribution and excretion route> of cancer vaccine lipoplex-RNA following intravenous injection of 14C-DOTMA-lipoplex-mRNA in mice." Cancer Research 83, no. 8_Supplement (April 14, 2023): LB242. http://dx.doi.org/10.1158/1538-7445.am2023-lb242.

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Abstract Messenger RNA (mRNA) has emerged as a new class of therapeutic agent delivered by a carrier lipoplex (LPX) to elicit an immune-response for treating various diseases, including cancers. However, the PK and tissue distribution of the components is not well characterized given its therapeutic novelty and structural complexity. As such, this study aimed to characterize the distribution and metabolic fate of LPX-mRNA using a radiolabeled DOTMA, a component of the LPX-mRNA therapeutic, to aid the development of this anti-cancer agent. To track the fate of LPX-mRNA, DOTMA was first radiolabeled with [14C] through chemical synthesis (14C-DOTMA, and then mixed with DOPE and mRNA at a specific ratio to form 14C-DOTMA-LPX-mRNA (14C-LPX-mRNA)). The plasma protein binding and blood cell partitioning for both 14C-LPX-mRNA and 14C-DOTMA alone were assessed in vitro. Moreover, the in vivo biodistribution and elimination of both 14C-molecules were characterized following a single intravenous (IV) injection in mice up to 12 weeks.The in-vitro assays showed the 14C-DOTMA and the 14C-LPX-mRNA were highly associated with plasma proteins and blood cell as the complexes were spun down at a much higher level as compared to in PBS solution (~5% and ~60% plasma proteins bound and ~60% and ~80% blood cell partitioned in 14C-DOTMA and the 14C-LPX-mRNA, respectively). Following in-vivo dosing in mice, plasma radioactivity of both test molecules showed a biphasic elimination profile with a rapid phase of decrease during the first 3 days followed by a prolonged exposure phase. The radioactivity in the whole blood and plasma displayed similar profiles but had minimal partitioning to blood cells, differing from the in-vitro data. We hypothesized that, both drug substances began to associate with plasma proteins/blood cells, then quickly distributed to the tissues and eliminated from the systemic circulation. Among all tissues analyzed, the liver and spleen showed the highest radioactivity levels where the 14C-LPX-mRNA peaked within the day while 14C-DOTMA peaked at 3-weeks-after-dose, followed by a long persistency. Lower levels of distribution and persistence of radioactivity were also observed in other tissues. The route of elimination is mainly through the biliary-fecal route with minimal contribution from the renal route for 14C-LPX-mRNA. 14C-LPX-mRNA achieved mass balance at 8-weeks after dose where ~70% was eliminated through feces, 3% through urine and ~20% remaining in tissues. 14C-DOTMA animals have an under-recovery of about 40-50% in radioactivity due to animals’ low intake of food and water which caused a severe reduction in animals’ weight. In summary, this study fully characterized the fate of the 14C-DOTMA and the 14C-LPX-mRNA in vitro and in vivo in mice. Our data demonstrated that the LPX-mRNA (by tracking DOTMA) mainly distributed to the spleen and liver with a long persistency, consistent with previous study showing the spleen as the major tissue for mRNA distribution. However, the LPX’s elimination profile (duration/persistency) is likely very different from that of mRNA. The ongoing work is to track the fate of mRNA component in LPX-mRNA, which could provide more insight on the correlation of DOTMA and mRNA, and help the development of this novel therapeutic modality. Citation Format: Victor Yip, Gillie Roth, Elizabeth Torres, Sara Wichner, Craig Blanchette, Amrita Kamath, Ben-Quan Shen. Characterizing the fate<tissue distribution and excretion route> of cancer vaccine lipoplex-RNA following intravenous injection of 14C-DOTMA-lipoplex-mRNA in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB242.

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He, Siyan, Shan Xia, Xiangrong Song, Hai Huang, Xueyan Wang, Xuehua Jiang, and Zhaohui Jin. "Investigating the Fate of MP1000-LPX In Vivo by Adding Serum to Transfection Medium." Pharmaceutical Nanotechnology 8, no. 5 (November 19, 2020): 399–408. http://dx.doi.org/10.2174/2211738508666200907105224.

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Background: Cationic liposomes (CLs) based messenger RNA (mRNA) vaccine has been a promising approach for cancer treatment. However, rapid lung accumulation after intraveous injection and significantly decreased transfection efficacy (TE) in serum substantially hamper its application. Objective: In this study, we attempt to investigate the fate of Mannose-PEG1000-lipoplex (MP1000-LPX) in vivo, a previous reported mRNA vaccine, and potential mechanism in it. Methods: MP1000-CLs and different type of MP1000-LPX were produced by previous method and characterized by dynamic light scattering (DLS). Organ distribution and Luc-mRNA expression of DiD loaded luciferase (Luc-mRNA)-MP1000-LPX were evaluated by IVIS Spectrum imaging system. Cellular transfection and uptake under serum-free and serum-containing conditions were analysed by flow cytometry and counted by FlowJo software. Results: MP1000-CLs had an average size of 45.3 ± 0.9 nm, a positive charge of 39.9 ± 0.9 mV. When MP1000-LPX formed, the particle size increased to about 130 nm, and zeta potential decreased to about 30 mV. All formulations were in narrow size distribution with PDI < 0.3. 6 h after intraveous injection, Luc-MP1000-LPX mostly distributed to liver, lung and spleen, while only successfully expressed Luc in lung. DC2.4 cellular transfection assay indicated serum substantially lowered TE of MP1000-LPX. However, the cellular uptake on DC2.4 cells was enhanced in the presence of serum. Conclusion: MP1000-LPX distributed to spleen but failed to transfect. Because serum dramatically decreased TE of MP1000-LPX on DC2.4 cells, but not by impeding its interaction to cell membrane. Serum resistance and avoidance of lung accumulation might be prerequisites for CLs based intravenous mRNA vaccines. Lay Summary: mRNA vaccine has been promising immunotherapy to treat cancer by delivering mRNA encoding tumor antigens to APCs and activating immune system against tumor cells. We are investigating the in vivo fate of MP1000-LPX, a CLs based mRNA vaccine. To see if serum causes the fate, we’ll be looking at the influence of serum on transfection and uptake efficacy of MP1000-LPX by DC2.4 cells experiments in vitro. Our findings will imply that serum inhibits transfection but not by decreasing uptake. Thus, we can ultilize serum to enhance transfection if we make intracellular process of MP1000-LPX successful.

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Collier, Ann E., Dan F. Spandau, and Ronald C. Wek. "Translational control of a human CDKN1A mRNA splice variant regulates the fate of UVB-irradiated human keratinocytes." Molecular Biology of the Cell 29, no. 1 (January 2018): 29–41. http://dx.doi.org/10.1091/mbc.e17-06-0362.

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In response to sublethal ultraviolet B (UVB) irradiation, human keratinocytes transiently block progression of the cell cycle to allow ample time for DNA repair and cell fate determination. These cellular activities are important for avoiding the initiation of carcinogenesis in skin. Central to these processes is the repression of initiation of mRNA translation through GCN2 phosphorylation of eIF2α (eIF2α-P). Concurrent with reduced global protein synthesis, eIF2α-P and the accompanying integrated stress response (ISR) selectively enhance translation of mRNAs involved in stress adaptation. In this study, we elucidated a mechanism for eIF2α-P cytoprotection in response to UVB in human keratinocytes. Loss of eIF2α-P induced by UVB diminished G1 arrest, DNA repair, and cellular senescence coincident with enhanced cell death in human keratinocytes. Genome-wide analysis of translation revealed that the mechanism for these critical adaptive responses by eIF2α-P involved induced expression of CDKN1A encoding the p21 (CIP1/WAF1) protein. We further show that human CDKN1A mRNA splice variant 4 is preferentially translated following stress-induced eIF2α-P by a mechanism mediated in part by upstream ORFs situated in the 5′-leader of CDKN1A mRNA. We conclude that eIF2α-P is cytoprotective in response to UVB by a mechanism featuring translation of a specific splice variant of CDKN1A that facilitates G1 arrest and subsequent DNA repair.

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50

Soucek, Sharon, Yi Zeng, Deepti L. Bellur, Megan Bergkessel, Kevin J. Morris, Qiudong Deng, Duc Duong, et al. "Evolutionarily Conserved Polyadenosine RNA Binding Protein Nab2 Cooperates with Splicing Machinery To Regulate the Fate of Pre-mRNA." Molecular and Cellular Biology 36, no. 21 (August 15, 2016): 2697–714. http://dx.doi.org/10.1128/mcb.00402-16.

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Numerous RNA binding proteins are deposited onto an mRNA transcript to modulate posttranscriptional processing events ensuring proper mRNA maturation. Defining the interplay between RNA binding proteins that couple mRNA biogenesis events is crucial for understanding how gene expression is regulated. To explore how RNA binding proteins control mRNA processing, we investigated a role for the evolutionarily conserved polyadenosine RNA binding protein, Nab2, in mRNA maturation within the nucleus. This study reveals thatnab2mutant cells accumulate intron-containing pre-mRNAin vivo. We extend this analysis to identify genetic interactions between mutant alleles ofnab2and genes encoding a splicing factor,MUD2, and RNA exosome,RRP6, within vivoconsequences of altered pre-mRNA splicing and poly(A) tail length control. As further evidence linking Nab2 proteins to splicing, an unbiased proteomic analysis of vertebrate Nab2, ZC3H14, identifies physical interactions with numerous components of the spliceosome. We validated the interaction between ZC3H14 and U2AF2/U2AF65. Taking all the findings into consideration, we present a model where Nab2/ZC3H14 interacts with spliceosome components to allow proper coupling of splicing with subsequent mRNA processing steps contributing to a kinetic proofreading step that allows properly processed mRNA to exit the nucleus and escape Rrp6-dependent degradation.

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