Elongator, a conserved complex required for wobble uridine modifications in Eukaryotes

Karlsborn, Tony; Tükenmez, Hasan; Mahmud, A. K. M. Firoj; Fu, Xu; Xu, Hao; Byström, Andeŕs S.

doi:10.4161/15476286.2014.992276

Cited by 109 publications

(109 citation statements)

References 110 publications

(169 reference statements)

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“…Elp3 is a tRAMEs [30] and loss of its activity impaired codon translation speed that triggers ER stress and activation of the PERK branch of the UPR in APs [29]. Although ER stress can interfere with cell migration [37], we were unable to detect the molecular readout of its activation in Elp3cKO-migrating neurons (Supplementary information, Figure S2C and S2D).…”

Section: Multiple Roles For Elongator During the Establishment Of Thementioning

confidence: 93%

“…Its nuclear roles include transcription elongation [24,25] and paternal genome demethylation [23]. In contrast, its main cytoplasmic role, described in yeast [26][27][28] and in mammals [29], is the promotion of tRNA modifications at the first nucleotide anticodon U34 (Elongator belongs to tRAMEs, an enzymatic cascade that promotes U34 tRNA anticodon side chain modifications) [30], thereby controlling mRNA translational efficiency in health [27] and disease [31]. Loss of Elongator activity leads to slowdown of translation resulting in proteotoxic stress [27].…”

Section: Introductionmentioning

confidence: 99%

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Elongator controls cortical interneuron migration by regulating actomyosin dynamics

et al. 2016

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The migration of cortical interneurons is a fundamental process for the establishment of cortical connectivity and its impairment underlies several neurological disorders. During development, these neurons are born in the ganglionic eminences and they migrate tangentially to populate the cortical layers. This process relies on various morphological changes that are driven by dynamic cytoskeleton remodelings. By coupling time lapse imaging with molecular analyses, we show that the Elongator complex controls cortical interneuron migration in mouse embryos by regulating nucleokinesis and branching dynamics. At the molecular level, Elongator fine-tunes actomyosin forces by regulating the distribution and turnover of actin microfilaments during cell migration. Thus, we demonstrate that Elongator cell-autonomously promotes cortical interneuron migration by controlling actin cytoskeletal dynamics.

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Section: Multiple Roles For Elongator During the Establishment Of Thementioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Elongator controls cortical interneuron migration by regulating actomyosin dynamics

et al. 2016

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“…BElongator^, a multimeric protein complex with methyl-transferase activity, participates in the first steps. BElongator^is also related to other cellular processes, such as elongation by RNA polymerase II, histone acetylation, telomeric gene silencing, and DNA repair (Chen et al 2011;Karlsborn et al 2014). Noteworthy in yeast, the phenotype produced by a defective U34 modification (morphological and growth alterations) was reverted by the overexpression of the involved tRNA (Klassen et al 2016b).…”

Section: The State Of the Trna Population In The Cellmentioning

confidence: 99%

Protein folding and tRNA biology

2017

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Polypeptides can fold into tertiary structures while they are synthesized by the ribosome. In addition to the amino acid sequence, protein folding is determined by several factors within the cell. Among others, the folding pathway of a nascent polypeptide can be affected by transient interactions with other proteins, ligands, or the ribosome, as well as by the translocation through membrane pores. Particularly, the translation machinery and the population of tRNA under different physiological or adaptive responses can dramatically affect protein folding. This review summarizes the scientific evidence describing the role of translation kinetics and tRNA populations on protein folding and addresses current efforts to better understand tRNA biology. It is organized into three main parts, which are focused on: (i) protein folding in the cellular context; (ii) tRNA biology and the complexity of the tRNA population; and (iii) available methods and technical challenges in the characterization of tRNA pools. In this manner, this work illustrates the ways by which functional properties of proteins may be modulated by cellular tRNA populations.

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“…4 The formation of mcm 5 s 2 U requires two genetically independent pathways, one depending on the Elongator complex and its interactors, the other depending on the sulfur transfer protein Urm1 and its sulfur donors (Nfs1, Tum1, Uba4) and acceptors (Ncs2, Ncs6). [5][6][7][8] Absence of either alone removes the mcm 5 -(Elongator) or the s 2 U part (Urm1) and induces overlapping defects including increased ribosomal frameshifting during mRNA translation, while elimination of both modification pathways severely aggravates these defects or may even cause synthetic lethality. 1,[9][10][11][12][13] Further, complete absence of mcm 5 s 2 U was shown to cause a substantial ribosomal slow down at the A-ending codons for Lys and Gln.…”

Section: Introductionmentioning

confidence: 99%

Combined tRNA modification defects impair protein homeostasis and synthesis of the yeast prion protein Rnq1

Schaffrath

Klassen

2017

Prion

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ABSTRACT. Modified nucleosides in tRNA anticodon loops such as 5-methoxy-carbonyl-methyl-2-thiouridine (mcm 5 s 2 U) and pseuduridine (C) are thought to be required for an efficient decoding process. In Saccharomyces cerevisiae, the simultaneous presence of mcm 5 s 2 U and C38 in tRNA Gln UUG was shown to mediate efficient synthesis of the Q/N rich [PIN C ] prion forming protein Rnq1.1 In the absence of these two tRNA modifications, higher than normal levels of hypomodified tRNA Gln UUG , but not its isoacceptor tRNA Gln CUG can restore Rnq1 synthesis. Moroever, tRNA overexpression rescues pleiotropic phenotypes that associate with loss of mcm 5 s 2 U and C38 formation. Notably, combined absence of different tRNA modifications are shown to induce the formation of protein aggregates which likely mediate severe cytological abnormalities, including cytokinesis and nuclear segregation defects. In support of this, overexpression of the aggregating polyQ protein Htt103Q, but not its non-aggregating variant Htt25Q phenocopies these cytological abnormalities, most pronouncedly in deg1 single mutants lacking C38 alone. It is concluded that slow decoding of particular codons induces defects in protein homeostasis that interfere with key steps in cytokinesis and nuclear segregation.

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Elongator, a conserved complex required for wobble uridine modifications in Eukaryotes

Cited by 109 publications

References 110 publications

Elongator controls cortical interneuron migration by regulating actomyosin dynamics

Elongator controls cortical interneuron migration by regulating actomyosin dynamics

Protein folding and tRNA biology

Combined tRNA modification defects impair protein homeostasis and synthesis of the yeast prion protein Rnq1

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