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Regulation of microRNA expression by the adaptor protein GRB2.

Published version
Peer-reviewed

Repository DOI


Type

Article

Change log

Authors

Stainthorp, Amy K 
Lin, Chi-Chuan 
Medhi, Ragini 
Ahmed, Zamal 

Abstract

Protein interactions with the microRNA (miRNA)-mediated gene silencing protein Argonaute 2 (AGO2) control miRNA expression. miRNA biogenesis starts with the production of precursor transcripts and culminates with the loading of mature miRNA onto AGO2 by DICER1. Here we reveal an additional component to the regulatory mechanism for miRNA biogenesis involving the adaptor protein, growth factor receptor-bound protein 2 (GRB2). The N-terminal SH3 domain of GRB2 is recruited to the PAZ domain of AGO2 forming a ternary complex containing GRB2, AGO2 and DICER1. Using small-RNA sequencing we identified two groups of miRNAs which are regulated by the binding of GRB2. First, mature and precursor transcripts of mir-17~92 and mir-221 miRNAs are enhanced. Second, mature, but not precursor, let-7 family miRNAs are diminished suggesting that GRB2 directly affects loading of these miRNAs. Notably, the resulting loss of let-7 augments expression of oncogenic targets such as RAS. Thus, a new role for GRB2 is established with implications for cancer pathogenesis through regulation of miRNA biogenesis and oncogene expression.

Description

Keywords

MicroRNAs, Gene Silencing, Base Sequence, GRB2 Adaptor Protein, Argonaute Proteins

Journal Title

Sci Rep

Conference Name

Journal ISSN

2045-2322
2045-2322

Volume Title

13

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (C57233/A22356)