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.
journal_name
Nat Struct Mol Bioljournal_title
Nature structural & molecular biologyauthors
Rau F,Freyermuth F,Fugier C,Villemin JP,Fischer MC,Jost B,Dembele D,Gourdon G,Nicole A,Duboc D,Wahbi K,Day JW,Fujimura H,Takahashi MP,Auboeuf D,Dreumont N,Furling D,Charlet-Berguerand Ndoi
10.1038/nsmb.2067subject
Has Abstractpub_date
2011-06-19 00:00:00pages
840-5issue
7eissn
1545-9993issn
1545-9985pii
nsmb.2067journal_volume
18pub_type
杂志文章abstract：:A fundamental question is how enzymes can accelerate chemical reactions. Catalysis is not only defined by actual chemical steps, but also by enzyme structure and dynamics. To investigate the role of protein dynamics in enzymatic turnover, we measured residue-specific protein dynamics in hyperthermophilic and mesophili...
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