Abstract
Muscleblind-like (MBNL) proteins are key regulators of precursor and mature mRNA metabolism in mammals. Based on published and novel data, we explore models of tissue-specific MBNL interaction with RNA. We portray MBNL domains critical for RNA binding and splicing regulation, and the structure of MBNL's normal and pathogenic RNA targets, particularly in the context of myotonic dystrophy (DM), in which expanded CUG or CCUG repeat transcripts sequester several nuclear proteins including MBNLs. We also review the properties of MBNL/RNA complex, including recent data obtained from UV cross-linking and immunoprecipitation (CLIP-Seq), and discuss how this interaction shapes normal MBNL-dependent alternative splicing regulation. Finally, we review how this acquired knowledge about the pathogenic RNA structure and nature of MBNL sequestration can be translated into the design of therapeutic strategies against DM.
Highlights
Muscleblind-like proteins (MBNL) belong to a family of tissue-specific RNA metabolism regulators, which in mammals are encoded by three genes MBNL1, MBNL2 and MBNL3 [Figure 1, [1,2]]
This is especially evident in the brain, heart and skeletal muscle, in which there is a several fold increase in MBNL1 and 2 mRNA expression in adult tissues compared to the fetal (Figure 2B)
Data generated in Drosophila indicate that myocyte enhancer factor 2 (MEF2) might be one of the transcription factors that drives the expression of MBNL1 [8]
Summary
Muscleblind-like proteins (MBNL) belong to a family of tissue-specific RNA metabolism regulators, which in mammals are encoded by three genes MBNL1, MBNL2 and MBNL3 [Figure 1, [1,2]]. In majority of tissues the mRNA level of MBNL1 and MBNL2 genes rises during differentiation This is especially evident in the brain, heart and skeletal muscle, in which there is a several fold increase in MBNL1 and 2 mRNA expression in adult tissues compared to the fetal (Figure 2B). Functional down-regulation of MBNLs in humans causes adult-to-fetal alternative splicing transition [12,13,14,15,16] This results in myotonic dystrophy [DM, [17,18,19,20,21]], which besides the striated muscle, affects other tissues, such as heart and brain. We highlight the structural basis of MBNL/RNA interaction with the implication for MBNL function in differentiation and disease, and discuss how this knowledge can be shaped into potential therapeutic approaches against DM
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