Arginine methylation of RNA-binding protein HuD by CARM1 regulates MN-1 differentiation through a post-transcriptional mechanism

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Title: Arginine methylation of RNA-binding protein HuD by CARM1 regulates MN-1 differentiation through a post-transcriptional mechanism
Authors: Hubers, Lisa
Date: 2010
Abstract: Spinal Muscular Atrophy results from loss of the survival of motor neuron (SMN) gene, leading to a deficiency in SMN protein and selective degeneration of motor neurons. We have found that coactivator-associated arginine methyltransferase 1 (CARM1) regulates the switch from proliferation to differentiation, downstream of neurotrophic signaling, in motor neuron-like cells. Here, through down-regulation of CARM1 levels, methylation of one of its substrates, HuD, is reduced, resulting in an increase in p21 mRNA. Methylation of HuD by CARM1 negatively regulates its direct interaction with p21 mRNA, the first demonstration that CARM1 can directly influence the RNA binding activity of a substrate. We have also identified a novel interaction between HuD and SMN. In MN-1 differentiation, we propose that SMN functions as an adaptor module through arginine methylation-regulated interactions with RNA binding proteins, including HuD, and that the formation of distinct mRNP complexes on mRNA are regulated either similarly or differentially by PRMTs and/or SMN. These findings may help to elucidate the specific role of arginine methylation and SMN in regulating differentiation of motor neurons and provide crucial insights into the cell-specific pathophysiology of spinal muscular atrophy.
URL: http://hdl.handle.net/10393/28632
http://dx.doi.org/10.20381/ruor-19366
CollectionTh├Ęses, 1910 - 2010 // Theses, 1910 - 2010
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