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U6 RNA biogenesis and disease association

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U6 snRNA is one of five uridine‐rich noncoding RNAs that form the major spliceosome complex. Unlike other U‐snRNAs, it reveals many distinctive aspects of biogenesis such as transcription by RNA polymerase III, transcript nuclear retention and particular features of transcript ends: monomethylated 5′‐guanosine triphosphate as cap structure and a 2′,3′‐cyclic phosphate moiety (>P) at the 3′ termini. U6‐snRNA plays a central role in splicing and thus its transcription, maturation, snRNP formation, and recycling are essential for cellular homeostasis. U6 snRNA enters the splicing cycle as part of the tri‐U4/U6.U5snRNP complex, and after significant structural arrangements forms the catalytic site of the spliceosome together with U2 snRNA and Prp8. U6 snRNA also contributes to the splicing reaction by coordinating metal cations required for catalysis. Many human diseases are associated with altered splicing processes. Disruptions of the basal splicing machinery can be lethal or lead to severe diseases such as spinal muscular atrophy, amyotrophic lateral sclerosis, or retinitis pigmentosa. Recent studies have identified a new U6 snRNA biogenesis factor Usb1, the absence of which leads to poikiloderma with neutropenia (PN) (OMIM 604173), an autosomal recessive skin disease. Usb1 is an evolutionarily conserved 3′→5′ exoribonuclease that is responsible for removing 3′‐terminal uridines from U6 snRNA transcripts, which leads to the formation of a 2′,3′ cyclic phosphate moiety (>P). This maturation step is fundamental for U6 snRNP assembly and recycling. Usb1 represents the first example of a direct association between a spliceosomal U6 snRNA biogenesis factor and human genetic disease.WIREs RNA 2013, 4:581–592. doi: 10.1002/wrna.1181 This article is categorized under: RNA Processing > 3' End Processing RNA in Disease and Development > RNA in Disease

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U6 snRNA undergoes extensive conformational changes during the splicing cycle. Secondary structures of human U6 snRNA in free single U6 snRNP with associated Lsm complex (a) U4/U6 di‐snRNP (b), and paired with U2 snRNA in the precatalytic spliceosome (c) model of the RNA–RNA interaction network within the active center of the yeast spliceosome before the first transesterification reaction (d). Evolutionarily invariant nucleotides within the human and yeast U6, U4, U2, and U5 snRNAs are marked in red, orange, green, and brown, respectively, while pre‐mRNA is colored in blue. The 3′ terminal cyclic phosphate (>P) is required for Lsm protein binding, with the relevant group shown in purple.
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U6 snRNA plays a central role in pre‐mRNA splicing through a dynamic cycle of canonical assembly and disassembly of the U2‐dependent spliceosome with U6 snRNP remodeling during the cycle. U6 snRNA remains in the nucleus and its biogenesis includes passage through the nucleoli and Cajal bodies. After formation of the active spliceosome, U6 snRNA plays a central role in splicing reactions as it participates in active site formation and binds divalent metal cations required for catalysis. See text for more details.
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Crystal structure of human Usb1 (Protein Data Bank (PDB) accession number 4H7W) confirmed previous bioinformatic predictions. The side chains of invariant catalytic histidines and serines from conserved HXT/S motifs are marked in red and green, respectively. Usb1 is comprised by an α/β‐type architecture that is common to the 2H family and is composed of two topologically equivalent repeats. The terminal lobe is composed of six anti‐parallel β‐sheets flanked by two α‐helices, while the transient lobe is formed by five anti‐parallel β‐sheets and two α‐helices.
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U6 snRNA reveals unique features of its biogenesis. (a) Schematic representation of the U6 gene structure with promoter and terminator sequences. Key regulatory elements within the promoter, specific transcription factor, and negative transcriptional regulator binding sites are shown. DSE, distal sequence element; PSE, proximal sequence element; Pol III, ‐RNA polymerase III. (b) Schematic representation of the U6 snRNA molecule secondary structure with its unique terminal features: monomethylated guanosine triphosphate at the 5′‐end and a 2′3′‐cyclic phosphate moiety at the 3′‐end. The 3′‐end processing of nascent U6 snRNAs includes the addition of UMP residues by a specific poly(U) polymerase and trimming by the Usb1 nuclease.
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RNA in Disease and Development > RNA in Disease
RNA Processing > 3′ End Processing

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