Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.
Nat Struct Mol Biol. 2011 Jun 19;18(7):840-5. doi: 10.1038/nsmb.2067.
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.
肌强直性营养不良是一种由 CUG 或 CCUG 重复扩展引起的 RNA 功能获得性疾病，这些重复会隔离 RNA 结合蛋白 MBNL1。在这里，我们描述了 MBNL1 的一个新发现的功能，作为 pre-miR-1 生物发生的调节剂，并发现肌强直性营养不良患者的心脏样本中的 miR-1 处理发生改变。MBNL1 结合位于 pre-miR-1 环内的 UGC 基序，并与 LIN28 竞争，LIN28 通过 ZCCHC11（TUT4）促进 pre-miR-1 的尿苷酸化，并阻止 Dicer 加工。由于 miR-1 的丢失，DM1 和 DM2 受累心脏中 miR-1 的靶标 GJA1（连接蛋白 43）和 CACNA1C（Cav1.2）的表达增加。CACNA1C 和 GJA1 分别编码心脏中的主要钙和间隙连接通道，我们提出它们的失调可能导致受影响个体中观察到的心脏功能障碍。
