Protein sequestration as a normal function of long noncoding RNAs

An emerging class of long noncoding RNAs (lncRNAs) function as decoy molecules that bind and sequester proteins thereby inhibiting their normal functions. Titration of proteins by lncRNAs has wide-ranging effects affecting nearly all steps in gene expression. While decoy lncRNAs play a role in normal physiology, RNAs expressed from alleles containing nucleotide repeat expansions can be pathogenic due to protein sequestration resulting in disruption of normal functions. Researchers from Baylor College of Medicine discuss commonalities between decoy lncRNAs that regulate gene expression by competitive inhibition of protein function through sequestration and specific examples of nucleotide repeat expansion disorders mediated by toxic RNA that sequesters RNA-binding proteins and impedes their normal functions. Understanding how noncoding RNAs compete with various RNA and DNA molecules for binding of regulatory proteins will provide insight into how similar mechanisms contribute to disease pathogenesis.

Protein sequestration by lncRNAs

 lncrna

aE. coli CsrB sRNA contains 22 GGA repeats (highlighted red) within secondary structures that bind and sequester up to nine CsrA dimers, inhibiting activation or repression of CsrA-responsive genes. b Nucleotides 400–598 of the Gas5 lncRNA form six hairpin structures, one of which contains two glucocorticoid response elements (GREs) that function as a GRE mimic (GREM, highlighted red) to bind and sequester activated glucocorticoid receptor (blue with yellow ligands), inhibiting transcriptional activity of GR. A mineralcorticoid response element (MRE) that potentially binds mineralcorticoid receptor is present in one of the six hairpin structures. c Representation of one repeat domain found in the NORAD lncRNA. Each domain contains one or two Pumilio response elements (PRE, highlighted red) that bind and sequester Pumilio proteins to regulate genomic stability

Morriss GR, Cooper TA. (2017) Protein sequestration as a normal function of long noncoding RNAs and a pathogenic mechanism of RNAs containing nucleotide repeat expansions. Hum Genet [Epub ahead of print]. [abstract]

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