Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

Molecular basis of titin exon exclusion by RBM20 and the novel titin splice regulator PTB4

[img]
Preview
PDF - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
4MB

Item Type:Article
Title:Molecular basis of titin exon exclusion by RBM20 and the novel titin splice regulator PTB4
Creators Name:Dauksaite, V. and Gotthardt, M.
Abstract:RNA-binding motif protein 20 (RBM20) is a cardiac splice regulator that adapts cardiac filling via its diverse substrates-including the sarcomeric protein titin. The molecular basis and regulation of RBM20-dependent exon exclusion are largely unknown. In tissue culture experiments, we show that the combination of RNA recognition motif (RRM) and C-terminus is necessary and sufficient for RBM20 activity, indicating an important function of the ZnF2 domain in splicing repression. Using splice reporter and in vitro binding assays targeting titin exons 241-243, we identified a minimal genomic segment that is necessary for RBM20-mediated splicing repression of the alternative exon. Here, RBM20 binds the cluster containing most RBM20 binding motifs through its RRM domain and represses the upstream and downstream introns. For subsequent exon exclusion, specific regions upstream, downstream and within the alternative exon 242 are required. Regulation of exon exclusion involves PTB4 as a novel titin splice regulator, which counteracts RBM20 repressor activity in HEK293 cells. Together, these mechanistic insights into the regulation and action of RBM20 and PTB4 provide a basis for the future development of RBM20 modulators that adapt titin elasticity in cardiac disease.
Source:Nucleic Acids Research
ISSN:0305-1048
Publisher:Oxford University Press (U.K.)
Date:6 March 2018
Official Publication:https://doi.org/10.1093/nar/gky165
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library