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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
Peter Feys, Gavin Giovannoni, Nathalie Dijsselbloem, Diego Centonze, Piet Eelen, Stine Lykke Andersen
BACKGROUND: Multiple sclerosis (MS) is a progressive disease associated with a large variety of symptoms and changing patients' needs during the disease course. In order to provide appropriate care in every disease stage and let patients live their lives to the full, a multi-disciplinary approach and patient activation is needed. OBJECTIVE: To summarise the multi-disciplinary perspective of MS, with focus on the organisation of a multi-disciplinary care team and possibilities to support patient activation...
August 2016: Multiple Sclerosis: Clinical and Laboratory Research
Marcos Arribas-Layton, Jaclyn Dennis, Eric J Bennett, Christian K Damgaard, Jens Lykke-Andersen
Processing bodies (PBs) are conserved cytoplasmic aggregations of translationally repressed mRNAs assembled with mRNA decay factors. The aggregation of mRNA-protein (mRNP) complexes into PBs involves interactions between low-complexity regions of protein components of the mRNPs. In Saccharomyces cerevisiae, the carboxy (C)-terminal Q/N-rich domain of the Lsm4 subunit of the Lsm1-7 complex plays an important role in PB formation, but the C-terminal domain of Lsm4 in most eukaryotes is an RGG domain rather than Q/N rich...
September 1, 2016: Molecular and Cellular Biology
Søren Lykke-Andersen, Yun Chen, Britt R Ardal, Berit Lilje, Johannes Waage, Albin Sandelin, Torben Heick Jensen
No abstract text is available yet for this article.
May 1, 2016: Genes & Development
Rui Fu, Myanna T Olsen, Kristofor Webb, Eric J Bennett, Jens Lykke-Andersen
The zinc finger protein tristetraprolin (TTP) promotes translation repression and degradation of mRNAs containing AU-rich elements (AREs). Although much attention has been directed toward understanding the decay process and machinery involved, the translation repression role of TTP has remained poorly understood. Here we identify the cap-binding translation repression 4EHP-GYF2 complex as a cofactor of TTP. Immunoprecipitation and in vitro pull-down assays demonstrate that TTP associates with the 4EHP-GYF2 complex via direct interaction with GYF2, and mutational analyses show that this interaction occurs via conserved tetraproline motifs of TTP...
March 2016: RNA
Marta Lloret-Llinares, Christophe K Mapendano, Lasse H Martlev, Søren Lykke-Andersen, Torben Heick Jensen
Most mammalian protein-coding gene promoters are divergent, yielding promoter upstream transcripts (PROMPTs) in the reverse direction from their conventionally produced mRNAs. PROMPTs are rapidly degraded by the RNA exosome rendering a general function of these molecules elusive. Yet, levels of certain PROMPTs are altered in stress conditions, like the DNA damage response (DDR), suggesting a possible regulatory role for at least a subset of these molecules. Here we manipulate PROMPT levels by either exosome depletion or UV treatment and analyze possible effects on their neighboring genes...
January 2, 2016: RNA Biology
Ying Wang, Marc Arribas-Layton, Yifang Chen, Jens Lykke-Andersen, George L Sen
In adult tissues, stem and progenitor cells must balance proliferation and differentiation to maintain homeostasis. How this is done is unclear. Here, we show that the DEAD box RNA helicase, DDX6 is necessary for maintaining adult progenitor cell function. DDX6 loss results in premature differentiation and decreased proliferation of epidermal progenitor cells. To maintain self-renewal, DDX6 associates with YBX1 to bind the stem loops found in the 3' UTRs of regulators of proliferation/self-renewal (CDK1, EZH2) and recruit them to EIF4E to facilitate their translation...
October 1, 2015: Molecular Cell
Søren Lykke-Andersen, Torben Heick Jensen
Nonsense-mediated mRNA decay (NMD) is probably the best characterized eukaryotic RNA degradation pathway. Through intricate steps, a set of NMD factors recognize and degrade mRNAs with translation termination codons that are positioned in abnormal contexts. However, NMD is not only part of a general cellular quality control system that prevents the production of aberrant proteins. Mammalian cells also depend on NMD to dynamically adjust their transcriptomes and their proteomes to varying physiological conditions...
November 2015: Nature Reviews. Molecular Cell Biology
Tao Huang, Kristian Traberg Larsen, Jens Richardt Møllegaard Jepsen, Niels Christian Møller, Anne Kaer Thorsen, Erik Lykke Mortensen, Lars Bo Andersen
OBJECTIVE: Adiposity may be associated with poorer cognitive function in children. The purpose of the study was to examine the effects of an obesity intervention on cognitive function in children. METHODS: One hundred and fifteen children were randomly allocated to either the Day Camp Intervention Arm (DCIA) or the Standard Intervention Arm (SIA). Children in the DCIA participated in a 6-week day camp intervention and a subsequent 46-week family-based intervention...
October 2015: Obesity
Suzanne R Lee, Gabriel A Pratt, Fernando J Martinez, Gene W Yeo, Jens Lykke-Andersen
RNA quality-control pathways get rid of faulty RNAs and therefore must be able to discriminate these RNAs from those that are normal. Here we present evidence that the adenosine triphosphatase (ATPase) cycle of the SF1 helicase Upf1 is required for mRNA discrimination during nonsense-mediated decay (NMD). Mutations affecting the Upf1 ATPase cycle disrupt the mRNA selectivity of Upf1, leading to indiscriminate accumulation of NMD complexes on both NMD target and non-target mRNAs. In addition, two modulators of NMD-translation and termination codon-proximal poly(A) binding protein-depend on the ATPase activity of Upf1 to limit Upf1-non-target association...
August 6, 2015: Molecular Cell
Stacy L Erickson, Elizabeth O Corpuz, Jeffrey P Maloy, Christy Fillman, Kristofer Webb, Eric J Bennett, Jens Lykke-Andersen
mRNA decapping is a central step in eukaryotic mRNA decay that simultaneously shuts down translation initiation and activates mRNA degradation. A major complex responsible for decapping consists of the decapping enzyme Dcp2 in association with decapping enhancers. An important question is how the activity and accumulation of Dcp2 are regulated at the cellular level to ensure the specificity and fidelity of the Dcp2 decapping complex. Here, we show that human Dcp2 levels and activity are controlled by a competition between decapping complex assembly and Dcp2 degradation...
June 2015: Molecular and Cellular Biology
Melissa A Hausburg, Jason D Doles, Sandra L Clement, Adam B Cadwallader, Monica N Hall, Perry J Blackshear, Jens Lykke-Andersen, Bradley B Olwin
Skeletal muscle satellite cells in their niche are quiescent and upon muscle injury, exit quiescence, proliferate to repair muscle tissue, and self-renew to replenish the satellite cell population. To understand the mechanisms involved in maintaining satellite cell quiescence, we identified gene transcripts that were differentially expressed during satellite cell activation following muscle injury. Transcripts encoding RNA binding proteins were among the most significantly changed and included the mRNA decay factor Tristetraprolin...
2015: ELife
Kalodiah G Toma, Indrani Rebbapragada, Sébastien Durand, Jens Lykke-Andersen
The nonsense-mediated mRNA decay (NMD) pathway serves an important role in gene expression by targeting aberrant mRNAs that have acquired premature termination codons (PTCs) as well as a subset of normally processed endogenous mRNAs. One determinant for the targeting of mRNAs by NMD is the occurrence of translation termination distal to the poly(A) tail. Yet, a large subset of naturally occurring mRNAs contain long 3' UTRs, many of which, according to global studies, are insensitive to NMD. This raises the possibility that such mRNAs have evolved mechanisms for NMD evasion...
May 2015: RNA
Søren Lykke-Andersen, Yun Chen, Britt R Ardal, Berit Lilje, Johannes Waage, Albin Sandelin, Torben Heick Jensen
Eukaryotic RNAs with premature termination codons (PTCs) are eliminated by nonsense-mediated decay (NMD). While human nonsense RNA degradation can be initiated either by an endonucleolytic cleavage event near the PTC or through decapping, the individual contribution of these activities on endogenous substrates has remained unresolved. Here we used concurrent transcriptome-wide identification of NMD substrates and their 5'-3' decay intermediates to establish that SMG6-catalyzed endonucleolysis widely initiates the degradation of human nonsense RNAs, whereas decapping is used to a lesser extent...
November 15, 2014: Genes & Development
Jeremy E Wilusz, Jeffrey Wilusz
Production of multiple functional RNAs from a single primary transcript is an extremely efficient use of genetic information, although it complicates the ability of the cell to independently regulate the production of each RNA. For the case of small nucleolar RNAs (snoRNAs) encoded within introns of mRNA genes, Lykke-Andersen and colleagues (pp. 2498-2517) demonstrated that alternative splicing and the SMG6 endonuclease of the nonsense-mediated RNA decay pathway are key regulators that control which RNAs accumulate...
November 15, 2014: Genes & Development
Boris Reznik, Sandra L Clement, Jens Lykke-Andersen
The tristetraprolin (TTP) family of zinc-finger proteins, TTP, BRF1 and BRF2, regulate the stability of a subset of mRNAs containing 3'UTR AU-rich elements (AREs), including mRNAs coding for cytokines, transcription factors, and proto-oncogenes. To better understand the mechanism by which TTP-family proteins control mRNA stability in mammalian cells, we aimed to identify TTP- and BRF1-interacting proteins as potential TTP-family co-factors. This revealed hnRNP F as a prominent interactor of TTP and BRF1. While TTP, BRF1 and hnRNP F are all RNA binding proteins (RBPs), the interaction of hnRNP F with TTP and BRF1 is independent of RNA...
2014: PloS One
Jens Lykke-Andersen, Eric J Bennett
The correct decoding of messenger RNAs (mRNAs) into proteins is an essential cellular task. The translational process is monitored by several quality control (QC) mechanisms that recognize defective translation complexes in which ribosomes are stalled on substrate mRNAs. Stalled translation complexes occur when defects in the mRNA template, the translation machinery, or the nascent polypeptide arrest the ribosome during translation elongation or termination. These QC events promote the disassembly of the stalled translation complex and the recycling and/or degradation of the individual mRNA, ribosomal, and/or nascent polypeptide components, thereby clearing the cell of improper translation products and defective components of the translation machinery...
February 17, 2014: Journal of Cell Biology
Christian Kroun Damgaard, Jens Lykke-Andersen
During recent years, it has become clear that regulation of mRNA stability is an important event in the control of gene expression. The stability of a large class of mammalian mRNAs is regulated by AU-rich elements (AREs) located in the mRNA 3' UTRs. mRNAs with AREs are inherently labile but as a response to different cellular cues they can become either stabilized, allowing expression of a given gene, or further destabilized to silence their expression. These tightly regulated mRNAs include many that encode growth factors, proto-oncogenes, cytokines, and cell cycle regulators...
2013: Cancer Treatment and Research
Susanne Rosendal, Erik Lykke Mortensen, Henrik Steen Andersen, Trond Heir
OBJECTIVE: This study used a questionnaire to identify individuals who met criteria for posttraumatic stress disorder (PTSD) ten months after surviving a disaster and compared their use of health care services before and after the disaster with that of survivors who did not meet criteria for PTSD. METHODS: Ten months after the December 26, 2004, Southeast Asian tsunami, Danish tourists who had been in areas exposed to the disaster were mailed a questionnaire asking about demographic characteristics and exposure to the tsunami...
January 1, 2014: Psychiatric Services: a Journal of the American Psychiatric Association
Suzanne R Lee, Jens Lykke-Andersen
In the cell, mRNAs and non-coding RNAs exist in association with proteins to form ribonucleoprotein (RNP) complexes. Regulation of RNP stability and function is achieved by alterations to the RNP through poorly understood mechanisms into which recent studies have now begun to provide insight. This emerging body of work points to chemical modification of RNPs at the RNA or protein level and ATP-dependent RNP remodeling by RNA helicases/RNA-dependent ATPases as central events that dictate RNA fate. Some RNP modifications serve as tags for recruitment of regulatory proteins, with RNP modifiers and recruited proteins analogous to the writers and readers of chromatin modification, respectively...
October 2013: Trends in Cell Biology
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