期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 18, 期 7, 页码 840-U120出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2067
关键词
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资金
- Institut National de la Sante et de la Recherche Medicale (INSERM) AVENIR
- Agence nationale de la recherche (ANR) GENOPAT [P007942]
- Association Francaise contre les Myopathies (AFM) [MNM1-12982]
- UPMC
- US National Institutes of Health (NIH) [P30 AR057220]
- Muscular Dystrophy Center Core Laboratories
- Ministere de l'enseignement superieur et de la recherche
- University of Strasbourg
- Ministry of Health, Labour and Welfare, Japan
- Grants-in-Aid for Scientific Research [23591245] Funding Source: KAKEN
Myotonic dystrophy is an RNA gain-of-function disease caused by expanded CUG or CCUG repeats, which sequester the RNA binding protein MBNL1. Here we describe a newly discovered function for MBNL1 as a regulator of pre-miR-1 biogenesis and find that miR-1 processing is altered in heart samples from people with myotonic dystrophy. MBNL1 binds to a UGC motif located within the loop of pre-miR-1 and competes for the binding of LIN28, which promotes pre-miR-1 uridylation by ZCCHC11 (TUT4) and blocks Dicer processing. As a consequence of miR-1 loss, expression of GJA1 (connexin 43) and CACNA1C (Cav1.2), which are targets of miR-1, is increased in both DM1- and DM2-affected hearts. CACNA1C and GJA1 encode the main calcium-and gap-junction channels in heart, respectively, and we propose that their misregulation may contribute to the cardiac dysfunctions observed in affected persons.
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