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A G‐Rich element forms a G‐quadruplex and regulates BACE1 mRNA alternative splicing
Author(s) -
Fisette JeanFrançois,
Montagna Daniel R.,
Mihailescu MihaelaRita,
Wolfe Michael S.
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07680.x
Subject(s) - g quadruplex , alternative splicing , messenger rna , rna splicing , element (criminal law) , precursor mrna , computational biology , biology , microbiology and biotechnology , genetics , chemistry , rna , gene , dna , political science , law
J. Neurochem. (2012) 121 , 763–773. Abstract β‐Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the transmembrane aspartyl protease that catalyzes the first cleavage step in the proteolysis of the APP to the amyloid β‐protein (Aβ), a process involved in the pathogenesis of Alzheimer disease. BACE1 pre‐mRNA undergoes complex alternative splicing, the regulation of which is not well understood. We identified a G‐rich sequence within exon 3 of BACE1 involved in controlling splice site selection. Mutation of the G‐rich sequence decreased use of the normal 5′ splice site of exon 3, which leads to full‐length and proteolytically active BACE1, and increased use of an alternative splice site, which leads to a shorter, essentially inactive isoform. Nuclease protection assays, nuclear magnetic resonance, and circular dichroism spectroscopy revealed that this sequence folds into a G‐quadruplex structure. Several proteins were identified as capable of binding to the G‐rich sequence, and one of these, heterogeneous nuclear ribonucleoprotein H, was found to regulate BACE1 exon 3 alternative splicing and in a manner dependent on the G‐rich sequence. Knockdown of heterogeneous nuclear ribonucleoprotein H led to a decrease in the full‐length BACE1 mRNA isoform as well as a decrease in Aβ production from APP, suggesting new possibilities for therapeutic approaches to Alzheimer’s disease.