Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy

F Rau, F Freyermuth, C Fugier, JP Villemin… - Nature structural & …, 2011 - nature.com
F Rau, F Freyermuth, C Fugier, JP Villemin, MC Fischer, B Jost, D Dembele, G Gourdon
Nature structural & molecular biology, 2011nature.com
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 …
Abstract
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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