A single KH domain in Bicaudal-C links mRNA binding and translational repression functions to maternal development

Dowdle, Megan E.; Park, Sookhee; Imboden, Susanne Blaser; Fox, Catherine A.; Houston, Douglas; Sheets, Michael

doi:10.1242/dev.172486

Cited by 13 publications

(22 citation statements)

References 36 publications

(81 reference statements)

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“…Xl Bicc1 binding to the previously defined 32-nt Cripto-1 RNA binding site was assessed using a purified recombinant protein consisting of the N-terminal region of Xenopus laevis Bicc1 (aa 1-506, ( Xl Bicc1)), which encompasses the multi-KH RNA binding domain of Bicc1 (Dowdle et al, 2019) ( Fig.1A-B ) ( Fig.S1 ). The Xl Cripto-1 RNA substrate was labeled on its 5’ end with fluorescein to allow its detection in electromobility shift (EMSA) and fluorescence polarization assays ( Fig.1B-C ) (Dowdle et al 2017).…”

Section: Resultsmentioning

confidence: 99%

“…In support of this idea, experimental analyses reveal that both RNA sequence and structural features of the Cripto-1 RNA site are important for Bicc1 recognition (Zhang et al 2014). Furthermore, each of the KH domains within the Bicc1 RNA binding domain is essential for Cripto-1 RNA binding, but only the conserved GXXG motif of the most conserved KH domain, the KH2 domain, is required (Dowdle et al 2019). Thus the additional KH domains must directly and/or indirectly provide for an additional non-paradigmatic (i.e.…”

Section: Introductionmentioning

confidence: 99%

“…The data reveal that the Xl Bicc1 binds to the defined Xl Cripto-RNA Bicc1 site via an interaction requiring at least two distinct protein-RNA interfaces. The first protein-RNA interface requires the GXXG motif within the KH2 domain of Xl Bicc1, suggesting that it occurs via the canonical KH-RNA interaction mechanism used by single KH domain RNA binding proteins (Dowdle et al 2019; Minegishi et al 2021). The second interface required the KH1 domain but not KH1’s GXXG motif, suggesting that KH1 promoted the formation of a second GXXG-independent protein-RNA interface.…”

Section: Introductionmentioning

confidence: 99%

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Conserved and diverged mechanisms for RNA target-site recognition by the multi KH-domain Bicaudal C protein

Dowdle

Tonelli

Fox

et al. 2022

Preprint

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The Bicaudal-C (Bicc1) multi-KH domain RNA binding protein controls cell fates by binding and repressing the translation of specific target mRNAs. To provide new insights into Bicc1-RNA binding we used quantitative assays to analyze interactions between Xenopus Bicc1 protein and the 32-nt Bicc1 RNA target site from XlCripto-1 mRNA. High-affinity binding by XlBicc1(Kd=34nM) required both a 5′ leader sequence and a 3′ loop sequence. Bicc1 proteins from humans (HsBicc1), zebrafish (DrBicc1) and fruit flies (DmBicc1) also bound the XlCripto-1 RNA with high-affinity via an interaction requiring the 5′ leader sequence, providing evidence for a conserved mechanism of RNA recognition by Bicc1. However, in contrast to XlBicc1, each of the other species' Bicc1s showed a significantly relaxed requirement for the 3′ loop sequence. Analyses of mutant forms of XlBicc1, revealed that the KH1 domain promoted Bicc1's requirement for the loop sequence via a GXXG-independent mechanism. In addition, a fusion protein comprised of the XlKH1 and the DmBicc1-KH2-KH3 subdomains was sufficient to establish high-affinity, loop-sensitive Bicc1-binding to XlCripto-1 RNA. These data support a model wherein the KH2 domain interacts with the leader sequence via a GXXG-mediated KH-RNA interface, defining the conserved core of the metazoan Bicc1-RNA interaction, while the KH1 domain is required for the formation of a more flexible, secondary protein-RNA interface that allows recognition of the 3′ loop sequence. This secondary interface differs between species and possibly between target mRNAs, establishing the potential for a range of translational repression activities for Bicc1 target mRNAs.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Conserved and diverged mechanisms for RNA target-site recognition by the multi KH-domain Bicaudal C protein

Dowdle

Tonelli

Fox

et al. 2022

Preprint

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“…BICC1 is a conserved RNA-binding protein that represses translation of selected mRNAs to control development [271][272][273][274][275]; the domains responsible for RNA binding are, however, partly lost during the chromosomal rearrangement, suggesting that this function is lost with the FGFR2-BICC1 fusion. Deletion of BICC1 leads to classical ciliopathy features, including randomization of the left-right asymmetry, and cystic development in the kidney, liver and pancreas [276][277][278][279][280][281][282][283].…”

Section: Fgfr2-bicc1mentioning

confidence: 99%

Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling

Niţă

Abraham

Krejčı́

et al. 2021

Cells

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A single primary cilium projects from most vertebrate cells to guide cell fate decisions. A growing list of signaling molecules is found to function through cilia and control ciliogenesis, including the fibroblast growth factor receptors (FGFR). Aberrant FGFR activity produces abnormal cilia with deregulated signaling, which contributes to pathogenesis of the FGFR-mediated genetic disorders. FGFR lesions are also found in cancer, raising a possibility of cilia involvement in the neoplastic transformation and tumor progression. Here, we focus on FGFR gene fusions, and discuss the possible mechanisms by which they function as oncogenic drivers. We show that a substantial portion of the FGFR fusion partners are proteins associated with the centrosome cycle, including organization of the mitotic spindle and ciliogenesis. The functions of centrosome proteins are often lost with the gene fusion, leading to haploinsufficiency that induces cilia loss and deregulated cell division. We speculate that this complements the ectopic FGFR activity and drives the FGFR fusion cancers.

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“…KH domain superfamily contains 14 families. KH domain can bind to RNA or DNA [ 4 , 5 ], and exists in different types of proteins, which play important roles in biological processes, including splicing, transcriptional regulation [ 6 , 7 , 8 , 9 ]. Now KH family genes haven’t been investigated in plant species systematically.…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Characterization and Expression Analysis of KH Family Genes Response to ABA and SA in Arabidopsis thaliana

Zhang

Liu

et al. 2022

IJMS

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K-homologous (KH) family is a type of nucleic acid-binding protein containing the KH domain and has been found to affect splicing and transcriptional regulation. However, KH family genes haven’t been investigated in plant species systematically. In this study, we identified 30 genes that belonged to the KH family based on HMM of the KH domain in Arabidopsis thaliana. Phylogenetic tree analysis showed that the KH family is grouped into three subgroups. Synteny analysis showed that AtKH9 and AtKH29 have the conserved synteny relationship between A. thaliana and the other five species. The AtKH9 and AtKH29 were located in the cytoplasm and nucleus. The seed germination rates of the mutants atkh9 and atkh29 were higher than wild-type after abscisic acid (ABA) and salicylic acid (SA) treatments. In addition, the expression of ABA-related genes, such as ABRE-binding factor 2 (ABF2), ABRE-binding factor 4 (ABF4), and delta 1-pyrroline-5-carboxylate synthase (P5CS), and an SA-related gene pathogenesis-related proteins b (PR1b) were downregulated after ABA and SA treatments, respectively. These results suggested that atkh9 and atkh29 mutants inhibit the effect of ABA and SA on seed germination. In conclusion, our results provide valuable information for further exploration of the function of KH family genes and propose directions and ideas for the identification and characterization of KH family genes in other plants.

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A single KH domain in Bicaudal-C links mRNA binding and translational repression functions to maternal development

Cited by 13 publications

References 36 publications

Conserved and diverged mechanisms for RNA target-site recognition by the multi KH-domain Bicaudal C protein

Conserved and diverged mechanisms for RNA target-site recognition by the multi KH-domain Bicaudal C protein

Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling

Genome-Wide Characterization and Expression Analysis of KH Family Genes Response to ABA and SA in Arabidopsis thaliana

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