Expanded CUG repeat RNAs form hairpins that activate the double-stranded RNA-dependent protein kinase PKR

Tian, Bin; White, Robert J.; Xia, Tianbing; Welle, Stephen; Turner, Douglas H.; Mathews, Michael B.; Thornton, Charles A.

doi:10.1017/s1355838200991544

Cited by 227 publications

(225 citation statements)

References 39 publications

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“…Several CUG-repeat-binding proteins have been identified including muscleblind, CUG-binding protein (CUG-BP), elav-type RNA binding protein 3 (ETR-3), which is 78% identical to CUG-BP, and protein kinase R (PKR; Timchenko et al 1996;Lu et al 1999;Miller et al 2000;Tian et al 2000). The proteins from three human muscleblind genes (Fardaei et al 2002) are homologs of a protein required for development of muscle and photoreceptor cells in Drosophila (Begemann et al 1997;Artero et al 1998).…”

Section: Myotonic Dystrophymentioning

confidence: 99%

Pre-mRNA splicing and human disease

Faustino¹,

Cooper²

2003

Genes Dev.

1,143

862

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The precision and complexity of intron removal during pre-mRNA splicing still amazes even 26 years after the discovery that the coding information of metazoan genes is interrupted by introns (Berget et al. 1977;Chow et al. 1977). Adding to this amazement is the recent realization that most human genes express more than one mRNA by alternative splicing, a process by which functionally diverse protein isoforms can be expressed according to different regulatory programs. Given that the vast majority of human genes contain introns and that most pre-mRNAs undergo alternative splicing, it is not surprising that disruption of normal splicing patterns can cause or modify human disease. The purpose of this review is to highlight the different mechanisms by which disruption of pre-mRNA splicing play a role in human disease. Several excellent reviews provide detailed information on splicing and the regulation of splicing (Burge et al. 1999;Hastings and Krainer 2001; Black 2003). The potential role of splicing as a modifier of human disease has also recently been reviewed (NissimRafinia and Kerem 2002). Constitutive splicing and the basal splicing machineryThe typical human gene contains an average of 8 exons. Internal exons average 145 nucleotides (nt) in length, and introns average more than 10 times this size and can be much larger (Lander et al. 2001). Exons are defined by rather short and degenerate classical splice-site sequences at the intron/exon borders (5Ј splice site, 3Ј splice site, and branch site; Fig. 1A). Components of the basal splicing machinery bind to the classical splice-site sequences and promote assembly of the multicomponent splicing complex known as the spliceosome. The spliceosome performs the two primary functions of splicing: recognition of the intron/exon boundaries and catalysis of the cut-and-paste reactions that remove introns and join exons. The spliceosome is made up of five small nuclear ribonucleoproteins (snRNPs) and >100 proteins. Each snRNP is composed of a single uridinerich small nuclear RNA (snRNA) and multiple proteins. The U1 snRNP binds the 5Ј splice site, and the U2 snRNP binds the branch site via RNA:RNA interactions between the snRNA and the pre-mRNA (Fig. 1B). Spliceosome assembly is highly dynamic in that complex rearrangements of RNA:RNA, RNA:protein, and protein:protein interactions take place within the spliceosome. Coinciding with these internal rearrangements, both splice sites are recognized multiple times by interactions with different components during the course of spliceosome assembly (for example, see Burge et al. 1999;Du and Rosbash 2002;Lallena et al. 2002;Liu 2002). The catalytic component is likely to be U6 snRNP, which joins the spliceosome as a U4/U6 · U5 tri-snRNP (Villa et al. 2002).A splicing error that adds or removes even 1 nt will disrupt the open reading frame of an mRNA; yet exons are correctly spliced from within tens of thousands of intronic nucleotides. This remarkable precision is, in part, built into the mechanism of intron removal because once...

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Section: Myotonic Dystrophymentioning

confidence: 99%

Pre-mRNA splicing and human disease

Faustino¹,

Cooper²

2003

Genes Dev.

1,143

862

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“…7), most likely to diminish their ability to interact with doublestranded RNA-binding proteins. Transcripts containing the uninterrupted double-stranded CAG repeats were shown earlier to activate the RNA-dependent protein kinase PKR (46,47), and form a complex with the specific 63 kDa CAG repeatbinding protein (48). Such interactions resulting in protein activation or sequestration were considered as effects potentially triggering the mechanism of RNA-mediated pathogenesis also in a group of neurodegenerative diseases caused by the CAG repeat expansions (17)(18)(19)(20)(21)49).…”

Section: Structures Of the Sca1 Transcripts Are The Same In Cellularmentioning

confidence: 99%

Imperfect CAG Repeats Form Diverse Structures in SCA1 Transcripts

Sobczak

Krzyżosiak

2004

Journal of Biological Chemistry

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The expanded CAG repeat in the coding sequence of the spinocerebellar ataxia type 1 (SCA1) gene is responsible for SCA1, one of the hereditary human neurodegenerative diseases. In the normal SCA1 alleles usually 1-3 CAT triplets break the continuity of the CAG repeat tracts. Here we show what is the structural role of the CAU interruptions in the SCA1 transcripts. Depending on their number and localization within the repeat tract the interruptions either enlarge the terminal loop of the hairpin formed by the repeats, nucleate the internal loops in its stem structure, or force the repeats to fold into two smaller hairpins. Thus, the interruptions destabilize the CAG repeat hairpin, which is likely to decrease its ability to participate in the putative RNA pathogenesis mechanism driven by the long CAG repeat hairpins.

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“…They suggested that CUG hairpins are the most stable structures formed and also that the DMPK mRNAs are sterically impeded from transport through nuclear pores, by giant hairpins or hairpin clusters formed by CUG repeats above a limit size (44 or less) (Koch & Leffert, 1998). Further thermal melting and nuclease mapping studies indicated that CUG repeats form highly stable hairpins (Tian et al, 2000). Michalowski et al, used electron microscopy to provide the first visual evidence that the DMPK mRNA expansion forms an RNA hairpin structure (Michalowski et al, 1999).…”

Section: Rna Nuclear Retentionmentioning

confidence: 99%