An RNA G-quadruplex in the 3' UTR of the proto-oncogene PIM1 represses translation

Arora, Amit; Suess, Beatrix

doi:10.4161/rna.8.5.16038

Cited by 69 publications

(56 citation statements)

References 29 publications

(33 reference statements)

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“…First, the parallel four-stranded structure of CRQ was demonstrated by CD spectroscopy from which the characteristic peaks at approximately 264 nm and 240 nm were observed ( Fig. 2A and B), which is consistent with previously reported RNA G-quadruplexes, [45][46][47][48][49][50][51][52][53]62 as well as by RNase T1 footprinting in which the involvement of three G-quartet planes in the formation of this secondary structure was demonstrated (Fig. 3A).…”

Section: Resultssupporting

confidence: 79%

Translational repression of cyclin D3 by a stable G-quadruplex in its 5′ UTR: implications for cell cycle regulation

et al. 2012

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cyclin D3 (CCND3) is one of the three D-type cyclins that regulate the G1/S phase transition of the cell cycle. Expression of CCND3 is observed in nearly all proliferating cells; however, the presence of high levels of CCND3 has been linked to a poor prognosis for several types of cancer. Therefore, further mechanistic studies on the regulation of CCND3 expression are urgently needed to provide therapeutic implications. In this study, we report that a conserved RNA G-quadruplex-forming sequence (hereafter CRQ), located in the 5' UTR of mammalian CCND3 mRNA, is able to fold into an extremely stable, intramolecular, parallel G-quadruplex in vitro. The CRQ G-quadruplex dramatically reduces the activity of a reporter gene in human cell lines, but it has little impact on its mRNA level, indicating a translational repression. Moreover, the CRQ sequence in its natural context inhibits translation of CCND3. Disruption of the G-quadruplex structure by G/U-mutation or deletion results in an elevated expression of CCND3 and an increased phosphorylation of Rb, a downstream target of CCND3, which promotes progression of cells through the G1 phase. Our results add to the growing understanding of the regulation of CCND3 expression and provide a potential therapeutic target for cancer treatment.

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Section: Resultssupporting

confidence: 79%

Translational repression of cyclin D3 by a stable G-quadruplex in its 5′ UTR: implications for cell cycle regulation

et al. 2012

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“…Surprisingly, a G-quadruplex in the 5′-UTR of the Transforming Growth Factor-beta (TGF-β2) was recently reported to augment translation (20). Furthermore, a G-quadruplex motif in the 3′-UTR of the proto-oncogene Pim1 was reported to repress translation in a similar manner as the majority of the G-quadruplexes in the 5′-UTR (21). For a complete survey of RNA G-quadruplexes in mRNAs, see (5).…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of RNA guanine-quadruplex binding proteins

Hacht

Seifert

Menger

et al. 2014

Nucleic Acids Research

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108

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Guanine quadruplex (G-quadruplex) motifs in the 5′ untranslated region (5′-UTR) of mRNAs were recently shown to influence the efficiency of translation. In the present study, we investigate the interaction between cellular proteins and the G-quadruplexes located in two mRNAs (MMP16 and ARPC2). Formation of the G-quadruplexes was confirmed by biophysical characterization and the inhibitory activity on translation was shown by luciferase reporter assays. In experiments with whole cell extracts from different eukaryotic cell lines, G-quadruplex-binding proteins were isolated by pull-down assays and subsequently identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. The binding partners of the RNA G-quadruplexes we discovered included several heterogenous nuclear ribonucleoproteins, ribosomal proteins, and splicing factors, as well as other proteins that have previously not been described to interact with nucleic acids. While most of the proteins were specific for either of the investigated G-quadruplexes, some of them bound to both motifs. Selected candidate proteins were subsequently produced by recombinant expression and dissociation constants for the interaction between the proteins and RNA G-quadruplexes in the low nanomolar range were determined by surface plasmon resonance spectroscopy. The present study may thus help to increase our understanding of the mechanisms by which G-quadruplexes regulate translation.

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“…These genes are involved in a wide variety of important biological processes and diseases (Table 2). G-quadruplexes mapped to 5′- or 3′-UTRs in these genes have been reported for their involvement in regulating 3′-end RNA processing [64,65], translation [11,24,31,66-69], or subcellular localization [36]. Table 2 shows human QGRS mapped to orthologous M. musculus genes along with their corresponding QGRS-conservation scores.…”

Section: Resultsmentioning

confidence: 99%

QGRS-Conserve: a computational method for discovering evolutionarily conserved G-quadruplex motifs

et al. 2014

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BackgroundNucleic acids containing guanine tracts can form quadruplex structures via non-Watson-Crick base pairing. Formation of G-quadruplexes is associated with the regulation of important biological functions such as transcription, genetic instability, DNA repair, DNA replication, epigenetic mechanisms, regulation of translation, and alternative splicing. G-quadruplexes play important roles in human diseases and are being considered as targets for a variety of therapies. Identification of functional G-quadruplexes and the study of their overall distribution in genomes and transcriptomes is an important pursuit. Traditional computational methods map sequence motifs capable of forming G-quadruplexes but have difficulty in distinguishing motifs that occur by chance from ones which fold into G-quadruplexes.ResultsWe present Quadruplex forming ‘G’-rich sequences (QGRS)-Conserve, a computational method for calculating motif conservation across exomes and supports filtering to provide researchers with more precise methods of studying G-quadruplex distribution patterns. Our method quantitatively evaluates conservation between quadruplexes found in homologous nucleotide sequences based on several motif structural characteristics. QGRS-Conserve also efficiently manages overlapping G-quadruplex sequences such that the resulting datasets can be analyzed effectively.ConclusionsWe have applied QGRS-Conserve to identify a large number of G-quadruplex motifs in the human exome conserved across several mammalian and non-mammalian species. We have successfully identified multiple homologs of many previously published G-quadruplexes that play post-transcriptional regulatory roles in human genes. Preliminary large-scale analysis identified many homologous G-quadruplexes in the 5′- and 3′-untranslated regions of mammalian species. An expectedly smaller set of G-quadruplex motifs was found to be conserved across larger phylogenetic distances. QGRS-Conserve provides means to build datasets that can be filtered and categorized in a variety of biological dimensions for more targeted studies in order to better understand the roles that G-quadruplexes play.

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An RNA G-quadruplex in the 3' UTR of the proto-oncogene PIM1 represses translation

Cited by 69 publications

References 29 publications

Translational repression of cyclin D3 by a stable G-quadruplex in its 5′ UTR: implications for cell cycle regulation

Translational repression of cyclin D3 by a stable G-quadruplex in its 5′ UTR: implications for cell cycle regulation

Identification and characterization of RNA guanine-quadruplex binding proteins

QGRS-Conserve: a computational method for discovering evolutionarily conserved G-quadruplex motifs

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