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Structural insights into CUG repeats containing the 'stretched U-U wobble': implications for myotonic dystrophy.

ABSTRACT: Tracks containing CUG repeats are abundant in human gene transcripts. Their biological role includes modulation of pre-mRNA splicing, mRNA transport and regulation of translation. Expanded forms of CUG runs are associated with pathogenesis of several neurodegenerative diseases, including myotonic dystrophy type 1. We have analysed two crystal structures of RNA duplexes containing the CUG repeats: G(CUG)(2)C and (CUG)(6). The first of the structures, analysed at 1.23 A resolution, is of an oligomer designed by us. The second model was obtained after 'detwinning' the 1.58 A X-ray data previously deposited in the PDB. The RNA duplexes are in the A-form in which all the C-G pairs form Watson-Crick interactions while all the uridine pairs can be described as U*U cis wobble having only one hydrogen bond between the bases. The residue, which accepts the H-bond, is inclined towards the minor groove. This previously unreported base pairing can be described as 'stretched U-U wobble'. The regular hydrogen-bonding pattern of interactions with the solvent, the electrostatic charge distribution and surface features indicate the ligand binding potential of the CUG tracks.

SUBMITTER: Kiliszek A

PROVIDER: S-EPMC2709583 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Structural insights into CUG repeats containing the 'stretched U-U wobble': implications for myotonic dystrophy.

Kiliszek Agnieszka A Kierzek Ryszard R Krzyzosiak Wlodzimierz J WJ Rypniewski Wojciech W

Nucleic acids research 20090511 12

Tracks containing CUG repeats are abundant in human gene transcripts. Their biological role includes modulation of pre-mRNA splicing, mRNA transport and regulation of translation. Expanded forms of CUG runs are associated with pathogenesis of several neurodegenerative diseases, including myotonic dystrophy type 1. We have analysed two crystal structures of RNA duplexes containing the CUG repeats: G(CUG)(2)C and (CUG)(6). The first of the structures, analysed at 1.23 A resolution, is of an oligom ...[more]

PMID: 19433512

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Project description:Myotonic dystrophy type 1 (DM1) is the most common type of adult muscular dystrophy caused by the expanded triple-nucleotides (CUG) repeats. Myoblast in DM1 displayed many defects, including defective myoblast differentiation, ribonuclear foci, and aberrant alternative splicing. Despite many were revealed to function in DM1, microRNAs that regulated DM1 via directly targeting the expanded CUG repeats were rarely reported. Here we discovered that miR-322/-503 rescued myoblast defects in DM1 cell model by targeting the expanded CUG repeats. First, we studied the function of miR-322/-503 in normal C2C12 myoblast cells. Downregulation of miR-322/-503 significantly hindered the myoblast differentiation, while miR-322/-503 overexpression promoted the process. Next, we examined the role of miR-322/-503 in the DM1 C2C12 cell model. miR-322/-503 was downregulated in the differentiation of DM1 C2C12 cells. When we introduced ectopic miR-322/-503 expression into DM1 C2C12 cells, myoblast defects were almost fully rescued, marked by significant improvements of myoblast differentiation and repressions of ribonuclear foci formation and aberrant alternative splicing. Then we investigated the downstream mechanism of miR-322/-503 in DM1. Agreeing with our previous work, Celf1 was proven to be miR-322/-503's target. Celf1 knockdown partially reproduced miR-322/-503's function in rescuing DM1 C2C12 differentiation but was unable to repress ribonuclear foci, suggesting other targets of miR-322/-503 existed in the DM1 C2C12 cells. As the seed regions of miR-322 and miR-503 were complementary to the CUG repeats, we hypothesized that the CUG repeats were the target of miR-322/-503. Through expression tests, reporter assays, and colocalization staining, miR-322/-503 was proved to directly and specifically target the expanded CUG repeats in the DM1 cell model rather than the shorter ones in normal cells. Those results implied a potential therapeutic function of miR-322/-503 on DM1, which needed further investigations in the future.

Dataset Information

Structural insights into CUG repeats containing the 'stretched U-U wobble': implications for myotonic dystrophy.

Publications

Structural insights into CUG repeats containing the 'stretched U-U wobble': implications for myotonic dystrophy.

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