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Emerging functions of the Quaking RNA‐binding proteins and link to human diseases

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RNA‐binding proteins (RBPs) are essential players in RNA metabolism including key cellular processes from pre‐mRNA splicing to mRNA translation. The K homology‐type QUAKING RBP is emerging as a vital factor for oligodendrocytes, monocytes/macrophages, endothelial cell, and myocyte function. Interestingly, the qkI gene has now been identified as the culprit gene for a patient with intellectual disabilities and is translocated in a pediatric ganglioglioma as a fusion protein with MYB. In this review, we will focus on the emerging discoveries of the QKI proteins as well as highlight the recent advances in understanding the role of QKI in human disease pathology including myelin disorders, schizophrenia and cancer. WIREs RNA 2016, 7:399–412. doi: 10.1002/wrna.1344 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease
The role of QKI in human diseases. Myelin disorders: QKI loss has been associated with defects in myelin formation and maintenance in rodents. Given the high conservation of the qkI gene between rodents and mice, a role for QKI in human myelination is predicted. The reduction in QKI levels at lesion sites could result in failure of newly generated oligodendrocyte precursors to differentiate and myelinate causing remyelination to fail. Schizophrenia: schizophrenic patients have been demonstrated to display pathological changes in myelin structure as well as decreased expression of myelin/oligodendrocyte genes. A reduction in QKI‐7 and QKI‐7b levels has been observed in schizophrenic patients. However, whether the decrease in QKI levels leads to reduced expression of myelin genes (and hence pathological myelin structure) or the abnormality in oligodendrocyte gene expression and function leads to oligodendrocyte death and hence reduced QKI levels remain to be investigated. 6q terminal deletion: a patient has been identified to harbor a balanced reciprocal translocation between chromosomes 5 and 6 that disrupts the qkI gene. The patient suffers from phenotypes similar to 6q terminal deletion with intellectual disabilities, hypotonia, seizures, brain anomalies and specific dysmorphic features. Defects in monocyte differentiation into macrophages are observed in the patient. Cancer: chromosomal deletions mapping to 6q25‐6q26 have been associated with cancer and were found in 30% of Glioblastoma multiforme. In addition, one pediatric ganglioglioma demonstrated a 6q23.3q26 deletion that was predicted to result in a MYB–QKI fusion. Restenosis/Atherosclerosis: increased QKI levels are observed in vascular smooth muscle cells in human restenotic lesions as well as in monocytes/macrophages in atherosclerotic lesions. Legend: solid lines indicate direct evidence. Dashed lines indicate a predicted association.
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The role of QKI in regulating several aspects of RNA metabolism. Alternative splicing: a schematic depicting a pre‐mRNA with exon 2 as the alternate exon. QKI functions as a trans‐acting factor to regulate alternative splicing by binding to Quaking response elements (QRE, shown in green), that are adjacent to the alternate exon. The binding of QKI to its QRE could either lead to exon inclusion or skipping. Solid lines depict constitutive splicing whereas dashed lines depict alternate splicing depending on either inclusion or exclusion. Circular RNA production: circular RNA formation occurs due to a noncanonical form of alternative splicing, where the splice donor site of one exon is back spliced to a splice acceptor site of an upstream exon. The binding of QKI to QREs adjacent to exons giving rise to the circRNA can mediate the circRNA formation. Micro‐RNA processing: one of the mechanisms by which QKI regulates miRNAs is by binding to its QRE in the pri‐microRNA which then functions to sequester the pri‐miRNA in the nucleus and inhibits further processing (example: pri‐miR‐7‐1), which in turn inhibits the formation of a mature miRNA and thus nuclear export into the cytoplasm. mRNA stability: QKI binding to its QREs in the 3′‐UTRs of mRNA could lead to either increasing or decreasing the stability of the mRNA. mRNA translation: QKI has been shown to bind to its QREs in the 3′‐UTR and function to enhance the translation of its bound mRNA.
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QKI is a sequence specific RNA binding protein. (a) Probability matrix (graphic logo) depicting the relative frequency of each residue at each position within the Quaking response element (QRE). (b) Crystal structure of the QKI RNA binding domain bound to the QRE. (Reprinted with permission from Ref . Copyright 2013 Cold Spring Harbor Laboratory Press)
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Structure of the qkI gene. A schematic showing the qkI locus with exons and introns. The alternative messages of qkI are shown. Name of distinct alternative transcripts are shown on the left.
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RNA in Disease and Development > RNA in Disease
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Processing > Splicing Regulation/Alternative Splicing

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