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PubMed2005

Sustained cadherin 23 expression in young and adult cochlea of normal and hearing-impaired mice.

Cadherin 23 encodes a single-pass transmembrane protein with 27 extracellular cadherin-domains and localizes to stereocilia where it functions as an inter-stereocilia link. Cadherin 23-deficient mice show congenital deafness in combination with circling behavior as a result of organizational defects in the stereocilia hair bundle; common inbred mouse strains carrying the hypomorphic Cdh23(753A) allele are highly susceptible to sensorineural hearing loss. Here, we show that an antibody (N1086) directed against the intracellular carboxyterminus reacts specifically with cadherin 23 and detects with high sensitivity the isoform devoid of the peptide encoded by exon 68 (CDH23Delta68). Cochlea, vestibule, eye, brain and testis produce the CDH23Delta68 isoform in abundance and form moieties with different molecular weight due to variations in glycosylation content. In the cochlea, CDH23Delta68 expression is highest at postnatal day 1 (P1) and P7; expression is down regulated through P14 and P21 and persists at a low steady-state level throughout adulthood (P160). Furthermore, CDH23Delta68 expression levels in young and adult cochlea are similar among normal and hearing deficient strains (C3HeB/FeJ, C57BL/6J and BUB/BnJ). Finally, by immunofluorescence using an antibody (Pb240) specific for ectodomain 14, we show that cadherin 23 localizes to stereocilia during hair bundle development in late gestation and early postnatal days. Cadherin 23-specific labeling becomes weaker as the hair bundle matures but faint labeling concentrated near the top of stereocilia is still detectable at P35. No labeling of cochlea stereocilia was observed with N1086. In conclusion, our data describe a cadherin 23-specific antibody with high affinity to the CDH23Delta68 isoform, reveal a dynamic cochlea expression and localization profile and show sustained cadherin 23 levels in adult cochlea of normal and hearing-impaired mice.

Amino Acid Sequence↗
PubMed2002

Genomic analysis of the terpenoid synthase ( AtTPS) gene family of Arabidopsis thaliana.

A family of 40 terpenoid synthase genes ( AtTPS) was discovered by genome sequence analysis in Arabidopsis thaliana. This is the largest and most diverse group of TPS genes currently known for any species. AtTPS genes cluster into five phylogenetic subfamilies of the plant TPS superfamily. Surprisingly, thirty AtTPS closely resemble, in all aspects of gene architecture, sequence relatedness and phylogenetic placement, the genes for plant monoterpene synthases, sesquiterpene synthases or diterpene synthases of secondary metabolism. Rapid evolution of these AtTPS resulted from repeated gene duplication and sequence divergence with minor changes in gene architecture. In contrast, only two AtTPS genes have known functions in basic (primary) metabolism, namely gibberellin biosynthesis. This striking difference in rates of gene diversification in primary and secondary metabolism is relevant for an understanding of the evolution of terpenoid natural product diversity. Eight AtTPS genes are interrupted and are likely to be inactive pseudogenes. The localization of AtTPS genes on all five chromosomes reflects the dynamics of the Arabidopsis genome; however, several AtTPS genes are clustered and organized in tandem repeats. Furthermore, some AtTPS genes are localized with prenyltransferase genes ( AtGGPPS, geranylgeranyl diphosphate synthase) in contiguous genomic clusters encoding consecutive steps in terpenoid biosynthesis. The clustered organization may have implications for TPS gene evolution and the evolution of pathway segments for the synthesis of terpenoid natural products. Phylogenetic analyses highlight events in the divergence of the TPS paralogs and suggest orthologous genes and a model for the evolution of the TPS gene family.

Alkyl and Aryl Transferases↗
PubMed2003

Genomic organization and embryonic expression of Igsf8, an immunoglobulin superfamily member implicated in development of the nervous system and organ epithelia.

Igsf8 is an immunoglobulin protein that binds to the tetraspanin molecules, CD81 and CD9. We describe the genomic organization of mouse and human Igsf8, and reveal a dynamic expression pattern during embryonic and fetal development. Igsf8 is first expressed at E9.5 in a ventral domain of the neural tube, with dorsal expression apparent at E10.5. We show that the ventral, but not the dorsal, domain of neural tube expression is dependent on Shh signaling. From E11.5, Igsf8 is expressed at the lateral edge of the ventricular zone, in early postmitotic neuroblasts, and in dorsal root and cranial ganglia. Igsf8 is also expressed in the branchial arches, dorsal pancreatic primordium, neural retina, olfactory epithelium, gut, kidney, and lung.

Animals↗
PubMed1993

A dynamical model for ribozyme function based on the sequential folding of pre-mRNA transcripts.

Making use of parallel Monte Carlo simulations of competing folding pathways, we determine the specific stages in the in vivo sequential folding of group I pre-mRNA transcripts where participation of a trans-acting factor or an already-assembled portion of the transcript itself is required to generate a catalytically competent structure and subsequently shape the 3' splicing site. Thus, the model for ribozyme function revealed by the simulations should be regarded as dynamical since it is based on sequential folding. Our main aim is to prove that sequential folding warrants the chronology of splicing events required for ribozyme function, a feature which cannot be reproduced in existing static models of folding based on free energy minimization. The effect of trans-acting factors on the catalytically relevant folding pathway is assessed by comparing the in vitro folding pathway with the pathway that leads to the structure that splices the 5' extremity. The latter has been inferred previously by other authors using phylogenetic analysis. Since our model is rooted in multiprocessed folding algorithms, we concentrate on mitochondrial pre-mRNA transcripts belonging to group I which undergo no detectable self-splicing in vitro. As an illustrative example, the results have been specialized to the fourth intron of the yeast apocytochrome b gene (YCOB4). A crucial feature of our approach, irreproducible in previous models, is that it accounts for a meaningful scenario of competition between hydrolysis at the 3' extremity of the intron and exon-exon ligation. We prove that this scenario explains how the premature formation of conserved helix P10 is prevented until 5' cleavage has taken place.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1997

Molecular domestication of mobile elements.

Transposable elements are ubiquitous in all organisms and represent a dynamic component of their genomes, causing mutations and thereby genetic variation. Because of their independent and expansive replication strategy, these elements are called selfish and were thought to have no impact on the adaptive evolution of their host organisms. Although most TE-induced mutations seem to exert only negative effects on the fitness of their carrier, recent evidence indicates that in the course of evolution at least some TE-mediated changes have become established features of the host genome. For example, the insertion of TEs may provide novel cis-regulatory regions to preexisting host genes or TE-derived trans-acting factors may undergo a molecular transition into novel host genes through a process described as molecular domestication. The stationary P element related gene clusters of D. guanche, D. madeirensis and D. subobscura provide an excellent model system to study the evolutionary impact of TEs on genome evolution. Each cluster unit consists of a cis-regulating section composed of different insertion sequences followed by the first three exons of a P element that are coding for a 66 kDa 'repressor-like' protein.

Animals↗
PubMed1997

[Recent progress in the diagnosis of growth hormone (GH) disorders].

Growth hormone (GH) disorders are characterized with clinical presentation of GH excess or deficiency. The pathogenesis and pathophysiology of GH disorders have been extensively studied with the sake of recent development of sensitive immunoassays and molecular cell biology. Highly sensitive immunoassays for GH have revealed the normal and abnormal GH secretory dynamics even under the detectable levels by conventional radioimmunoassay. Glucose loading clearly suppressed GH levels less than 1ng/ml in normal subjects. Clinical utility of insulin like growth factor-I (IGF-I) for diagnosing GH disorders was also evaluated. We have established the age- and sex-matched reference values of IGF-I and IGF binding protein-3 (IGFBP-3) in Japanese. Both IGF-I and IGFBP-3 had the similar diagnostic values for GH deficiency. Genetic alterations in GH secreting pituitary adenomas have been extensively studied. Gs alpha mutation has been found in about 30-40% of acromegaly. The prevalence of this mutation was previously considered low but recent studies showed even higher incidence in Japan. Other oncogenic mutations were considered rare in acromegaly. It is noteworthy that GH secreting adenoma tissues had high content of activated cyclic AMP responsive element-binding proteins (CREB). We have identified new mutation in GH-1 gene in patients with familial isolated GH deficiency type II, which resulted in the skipping of exon 3.

Acromegaly↗
PubMed2006

cDNA cloning and expression of the human NOBOX gene in oocytes and ovarian follicles.

Nobox is a homeobox gene that is preferentially expressed in the oocytes and is essential for folliculogenesis and the regulation of oocyte-specific gene expression in the mouse. The likely human homologue has been identified in silico but has not as yet been confirmed experimentally. Here, we present the first cDNA cloning and transcript expression analysis of the human NOBOX gene. Using RT-PCR, we reveal that expression within adult human tissues is limited to the ovary, testis and pancreas. Expression within the ovary is oocyte specific, with expression observed from the primordial stage ovarian follicle through to the metaphase II (MII) oocyte. In complementary studies, we reveal dynamic expression profiles of 14 additional homeobox genes throughout human oogenesis and early development. The expression of HOXA10 is restricted to primordial and early primary follicles. HOXB7 is expressed from primordial and early primary stage follicles through to germinal vesicle (GV) oocytes. Gastrulation brain homeobox 1 (GBX1) and HOXA7 genes are homeobox markers preferentially expressed by GV oocytes. HOXA1 and HEX are homeobox markers preferentially expressed by MII oocytes. In summary, the homeobox gene transcripts that are detected in ovarian follicles and oocytes are distinct from those expressed in human blastocysts (HOXB4, CDX2 and HOXC9) and granulosa cells (HOXC9, HOXC8, HOXC6, HOXA7, HOXA5 and HOXA4).

Base Sequence↗
PubMed2005

Gene identification in novel eukaryotic genomes by self-training algorithm.

Finding new protein-coding genes is one of the most important goals of eukaryotic genome sequencing projects. However, genomic organization of novel eukaryotic genomes is diverse and ab initio gene finding tools tuned up for previously studied species are rarely suitable for efficacious gene hunting in DNA sequences of a new genome. Gene identification methods based on cDNA and expressed sequence tag (EST) mapping to genomic DNA or those using alignments to closely related genomes rely either on existence of abundant cDNA and EST data and/or availability on reference genomes. Conventional statistical ab initio methods require large training sets of validated genes for estimating gene model parameters. In practice, neither one of these types of data may be available in sufficient amount until rather late stages of the novel genome sequencing. Nevertheless, we have shown that gene finding in eukaryotic genomes could be carried out in parallel with statistical models estimation directly from yet anonymous genomic DNA. The suggested method of parallelization of gene prediction with the model parameters estimation follows the path of the iterative Viterbi training. Rounds of genomic sequence labeling into coding and non-coding regions are followed by the rounds of model parameters estimation. Several dynamically changing restrictions on the possible range of model parameters are added to filter out fluctuations in the initial steps of the algorithm that could redirect the iteration process away from the biologically relevant point in parameter space. Tests on well-studied eukaryotic genomes have shown that the new method performs comparably or better than conventional methods where the supervised model training precedes the gene prediction step. Several novel genomes have been analyzed and biologically interesting findings are discussed. Thus, a self-training algorithm that had been assumed feasible only for prokaryotic genomes has now been developed for ab initio eukaryotic gene identification.

Algorithms↗
PubMed1996

De novo generation of simple sequence during gene amplification.

Mammalian cells that have undergone gene amplification and/or gene rearrangement have been used as resources to gain insight into the questions of chromosome structure and dynamics. The multidrug resistant murine cell line J7.V2-1 has been shown previously to contain two distinct forms of the highly amplified mdr2 gene, a member of the mouse gene family responsible for the multidrug resistant (MDR) phenotype [Kirschner, L. S. (1995) DNA Cell Biol. 14, 47-59]. Characterization of both forms of the gene revealed that one form corresponded to the wild-type structure of the gene, whereas the other represented a rearrangement. Investigation of this altered gene demonstrated a deletion of 1.6 kb of the wild-type sequence, and replacement of this region with a poly(AT) tract that appears to have been generated de novo. Analysis of the native sequence in this region demonstrated the absence of repetitive elements, but was notable for the presence of two long stretches of polypurine: polypyrimidine strand asymmetry. Analysis of mdr2 transcripts in this cell line revealed that nearly all of the mRNA is transcribed from the rearranged form of the gene. This message is unable to code for a functional mdr2 gene product, owing to a deletion of the fourth exon during this event. Mechanisms of the rearrangement, as well as the significance of this curious effect on transcription, are discussed.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1996

The tau proteins in neuronal growth and development.

The neuronal microtubule-associated protein tau has been implicated as having a role in the outgrowth of neural processes and the development of neuronal polarity. In vitro, tau promotes microtubule assembly, stabilizes cellular microtubules, and affects their dynamic behavior. Antisense experiments using cultured neurons provided evidence for an essential role of tau in the development of axons. However, tau knockout mice turned out to be surprisingly healthy and developed neurons which were functionally and structurally almost normal. This raises the question of how essential tau is for neuronal development. In the first part of this paper, data on the function of tau as a microtubule assembly-promoting and stabilizing factor are reviewed. Then, studies investigating the role of tau in the development of neuronal polarity are discussed. In the last part, recent results which provide evidence for a role of tau not directly related to its activity on microtubule assembly are summarized.

Aging↗
PubMed2003

Distinct promoter regions regulate spatial and temporal expression of the Drosophila caspase dronc.

DRONC is an apical Drosophila caspase essential for programmed cell death during fly development. During metamorphosis, dronc gene expression is regulated by the steroid hormone ecdysone, which also regulates the levels of a number of other critical cell death proteins. As DRONC protein levels are important in determining caspase activation and initiation of cell death, we have analyzed the regulation of the dronc promoter using transgenic flies expressing a LacZ reporter gene under the control of the dronc promoter. Our results indicate that dronc expression is highly dynamic during Drosophila development, and is controlled both spatially and temporally. We demonstrate that while a 2.3 kb dronc promoter region contains most of the information required for correct gene expression, a 1.1 kb promoter region is expressed in some tissues and not others. We further demonstrate that during larval-pupal metamorphosis, two ecdysone-induced transcription factors, Broad-Complex and E93, are required for correct dronc expression. Our data suggest that the dronc promoter is regulated in a highly complex manner, and provides an ideal system to explore the temporal and spatial regulation of gene expression driven by nuclear hormone receptors.

Animals↗
PubMed1985

Structural and functional studies of hemoglobin Poissy alpha 2 beta 2(56) (D7) Gly----Arg and 86 (F2) Ala----Pro.

Hemoglobin Poissy alpha 2 beta 2(56) (D7) Gly----Arg and 86 (F2) Ala----Pro, is a new variant of the beta chain with two substitutions within the second exon of the corresponding gene. The electrophoretic mobilities are identical to those of Hb Hamadan alpha 2 beta 2(56) (D7) Gly----Arg as is the fingerprint of the tryptic hydrolysate of the two abnormal beta chains. The second substitution beta 86 Ala----Pro was detected by high-pressure liquid chromatography. Hb Poissy has a threefold increase in oxygen affinity with low Hill coefficient and diminished Bohr effect, which are restored to normal upon addition of 2,3-bisphosphoglycerate. Since the functional properties of Hb Hamadan (beta 56 Gly----Arg) have been described as normal, the abnormal function of Hb Poissy may be attributed to the beta 86 (F2) Ala----Pro substitution. Hb Poissy exhibits a mild instability and a greater reactivity of the thiol groups of the beta 93 (F9) Cys residues in the deoxy form than does Hb A. The oxidation rate of Hb Poissy is biphasic indicating a large inequivalence between the alpha and beta hemes. Thereafter NMR studies demonstrated that the beta 86 Ala----Pro substitution produces a displacement of the F helix closer to the heme plane and a large increase in the dynamic fluctuations of the tertiary structure on the proximal side of the beta hemes. These results lead to the conclusion that the beta 86 Ala----Pro substitution produces a destabilization of the F helix extending downwards to the FG corner and altering both the beta hemes and the alpha 1 beta 2 contacts.

Amino Acids↗
PubMed1996

Factor VII central. A novel mutation in the catalytic domain that reduces tissue factor binding, impairs activation by factor Xa, and abolishes amidolytic and coagulant activity.

Factor VII is a vitamin K-dependent zymogen of a serine protease that participates in the initial phase of blood coagulation. A factor VII molecular variant (factor VII Central) was identified in a 24-year-old male with severe factor VII deficiency and whose plasma factor VII antigen was 38% of normal, but expressed <1% factor VII procoagulant activity. DNA sequence analysis of the patient's factor VII gene revealed a thymidine to cytidine transition at nucleotide 10907 in exon VIII that results in a novel amino acid substitution of Phe328 to Ser. The patient was homozygous for this mutation, whereas each parent of the patient was heterozygous for this mutation. To investigate the molecular properties of this variant, a recombinant F328S factor VII mutant was prepared and analyzed in relation to wild-type factor VII. F328S factor VII exhibited <1% factor VII procoagulant activity and a 2-fold decreased affinity for tissue factor and failed to activate factor X or IX in the presence of tissue factor following activation by factor Xa. In addition, F328S factor VIIa exhibited no detectable amidolytic activity in the presence of tissue factor. The rate of F328S factor VII activation by factor Xa was markedly decreased relative to the rate of wild-type factor VII activation as revealed by densitometry scanning of SDS gels. Temporal analysis of this reaction by SDS-polyacrylamide gel electrophoresis also revealed the formation of two novel F328S factor VII degradation products (40 and 9 kDa) resulting from factor Xa proteolysis of the Arg315-Lys316 peptide bond in intact F328S factor VII. Computer modeling and molecular dynamics simulations of the serine protease domain of factor VIIa suggested that the inability of F328S factor VIIa to cleave substrates may result from the apparent formation of a hydrogen bond between Tyr377 and Asp338, a residue at the bottom of the substrate-binding pocket important for the interaction of substrate arginine side chains with the enzyme. These findings suggest that Phe328, which is conserved in prothrombin, factor IX, factor X, factor VII, and trypsin, is important for factor VIIa catalysis.

Adult↗
PubMed2004

A gene highly expressed in tumor cells encodes novel structure proteins.

We isolated several related but distinct cDNA clones encoding novel structure proteins (NSP) when screening a cDNA library. Analysis revealed that these cDNAs and several similar ESTs in the public databases are derived from a single gene of 17 exons that span a minimum of 227-kb region. This gene is located at chromosome 17p11.2, a region frequently amplified in human gliomas and osteosarcomas, and involved in Birt-Hogg-Dube syndrome, a tumor-prone syndrome. The major coding sequences shared by all isolated transcripts are predicted to encode SMC (structural maintenance of chromosome)/SbcC ATPase motifs and coiled-coil domains commonly seen in motor or structure proteins. Two 5'-end and two 3'-end variants (type 5alpha/beta and 3alpha/beta, respectively) were identified, making a total of four possible transcripts. Both 5alpha and 5beta variants were detected in human testis mRNA, but only type 5alpha was detectable in RNA samples extracted from HeLa cells. The unique carboxyl-terminus of 3beta contains a Ca(2+)-dependent actin-binding domain. Immunohistochemistry studies revealed that NSPs were mostly localized to nuclei. Northern blot analysis demonstrated two major bands and the expression levels are tremendously high in testis while barely detectable in other normal tissues examined. Interestingly, NSP5alpha3alpha is highly expressed in some tumor cell lines. These results suggest that NSPs represent a new family of structure proteins with a possible role in nuclear dynamics during cell division, and that NSP5alpha3alpha may serve as a tumor marker.

Amino Acid Sequence↗
PubMed1998

Somatic hypermutation in mouse lambda chains.

The frequency and distribution of somatic hypermutation in immunoglobulin genes and the effect of amino acid substitution on the structure/function of antibodies were studied using hybridomas that secrete anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) monoclonal antibodies bearing lambda 1 chains. A high frequency of mutation was observed in V-J exons and J-C introns of rearranged and active lambda 1 chains but not in the 5'-non-coding regions of these chains. Since a similar distribution was observed in inactive lambda 2 chain genes, 5'-non-coding regions containing a promoter were considered to be protected from mutation in view of their apparent importance. Using transgenic mice carrying chloramphenicol acetyl transferase transgenes driven by the VH promoter and heavy-chain intron enhancer, it was also revealed that these cis-acting elements are important in the induction of somatic hypermutation and are capable of inducing mutation even in non-immunoglobulin genes. Affinity of anti-NP Abs to NP increased with time after immunization to approximately 8,000-fold (affinity maturation); however, fine specificity, such as heteroclicity, remained unchanged. Memory B cells, which are responsible for affinity maturation, were analyzed in terms of the mutation from Trp to Leu at position 33, a change known to raise affinity about 10-fold and considered to be a memory B-cell marker. These cells were found predominantly in the early stage (2-3-week) hybridomas but rarely in late stage (> 12-week) ones, suggesting that a dynamic change in the memory B-cell population occurs during the immunization process.

Animals↗
PubMed1994

The marsupial MHC: the tammar wallaby, Macropus eugenii, contains an expressed DNA-like gene on chromosome 1.

In the placental mammal major histocompatibility complex (MHC) three main families of class II genes, DR, DQ, and DP, have been recognized. Each family contains genes that code for one or more A- and B-chains. Recent evidence has indicated that a fourth family can be described, the DN/DO family. These four families arose sometime early in mammalian evolution. Our purpose was to deduce the MHC of an early mammalian ancestor of marsupials and eutherians. Using primers designed to conserved regions in exon 2 and exon 3 of the DQA gene we amplified an 830-bp band from the total genomic DNA of the marsupial, Macropus eugenii (tammar wallaby). However, sequence analysis of cloned genomic products showed that the primers had amplified three genes, two of which appeared to be alleles at one locus, while the other gene belonged to a closely related locus. Phylogenetic analysis showed that both these loci were most closely related to the human (HLA-DNA) and mouse (H-20a) DNA genes, with a bootstrap support of 78%. Expression of only one locus could be detected by RT-PCR from spleen RNA. In situ hybridization to tammar wallaby chromosomes mapped these genes to one region on the long arm of chromosome 1, indicating the position of the MHC in marsupials. Related A-chain genes were detected in monotremes, and human by southern blotting, and very faint bands were observed in the chicken. Hybridization with a tammar DNA-like gene on several marsupial species showed evidence of at least three DNA-like loci in the tammar wallaby, at least one in the koala, but none in the kowari. This indicates that the organization of the class II MHC may be more dynamic in marsupial than in placental mammals, but, in contrast to a previous study on the MHC of a marsupial, we cannot conclude that the class II gene families of placental and marsupial mammals evolved from different ancestral genes.

Amino Acid Sequence↗
PubMed2005

Integrating alternative splicing detection into gene prediction.

BACKGROUND: Alternative splicing (AS) is now considered as a major actor in transcriptome/proteome diversity and it cannot be neglected in the annotation process of a new genome. Despite considerable progresses in term of accuracy in computational gene prediction, the ability to reliably predict AS variants when there is local experimental evidence of it remains an open challenge for gene finders. RESULTS: We have used a new integrative approach that allows to incorporate AS detection into ab initio gene prediction. This method relies on the analysis of genomically aligned transcript sequences (ESTs and/or cDNAs), and has been implemented in the dynamic programming algorithm of the graph-based gene finder EuGENE. Given a genomic sequence and a set of aligned transcripts, this new version identifies the set of transcripts carrying evidence of alternative splicing events, and provides, in addition to the classical optimal gene prediction, alternative optimal predictions (among those which are consistent with the AS events detected). This allows for multiple annotations of a single gene in a way such that each predicted variant is supported by a transcript evidence (but not necessarily with a full-length coverage). CONCLUSIONS: This automatic combination of experimental data analysis and ab initio gene finding offers an ideal integration of alternatively spliced gene prediction inside a single annotation pipeline.

Algorithms↗
PubMed2026

A Conserved 3'UTR Stem-loop Directs UPF1/eIF4AIII-Dependent Regulation of GABARAPL1 mRNA.

RNA-binding proteins (RBP) interact with mRNA untranslated regions containing cis-regulatory elements to govern mRNA localization, stability, and translational efficiency. Among these trans-regulatory factors, RNA helicase UPF1 is a central factor which play a role in multiple mRNA decay pathways, including nonsense-mediated mRNA decay (NMD). NMD is triggered when an exon-junction complex (EJC) is located downstream of a premature termination codon. However, in some cases, NMD can be activated in an EJC-independent manner through mechanisms involving the 3'UTR. In the present study, we focused on the GABARAPL1 3'UTR, as previous studies had shown that this region plays a key role in NMD targeting, although the underlying molecular mechanism had not yet been elucidated. Unlike canonical NMD targets such as SC35, we found that the chemical inhibition of eIF4AIII helicase activity did not affect GABARAPL1 transcript levels, indicating that this transcript is regulated through its 3'UTR via an EJC-independent mechanism. We therefore investigated the potential presence of cis-regulatory element within the 3'UTR of GABARAPL1 which can regulate mRNA and protein levels in a UPF1-dependent manner. Furthermore, we identified a conserved RNA region spanning nucleotides 364-421 involved in GABARAPL1 targeting and used biochemical analysis to demonstrate the direct binding of UPF1 and eIF4AIII to this RNA region, to analyse its secondary structure in solution, and to map the protein-binding sites. By complementing these approaches with molecular modelling, we showed that this stem-loop adopts a stable global fold but a local flexibility and dynamic behaviour properties. Together, our results support the role of UPF1 and eIF4AIII as specific regulators of GABARAPL1 transcript and reveal a novel RNA regulatory element within its 3'UTR, which provides a completely unexpected binding site for these factors.

3' Untranslated Regions↗