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RNA and DNA G-quadruplexes bind to human Dicer and inhibit its activity;

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modified on 17.02.2021, 21:20
Guanine (G)-rich single-stranded nucleic acids can adopt G-quadruplex structures. Accumulating evidence indicates that G-quadruplexes serve important regulatory roles in fundamental biological processes such as DNA replication, transcription, and translation, while aberrant G-quadruplex formation is linked to genome instability and cancer. Understanding the biological functions played by G-quadruplexes requires detailed knowledge of their protein interactome. Here, we report that both RNA and DNA G-quadruplexes are bound by human Dicer in vitro. Using in vitro binding assays, mutation studies, and computational modeling we demonstrate that G-quadruplexes can interact with the Platform-PAZ-Connector helix cassette of Dicer, the region responsible for anchoring microRNA precursors (pre-miRNAs). Consequently, we show that G-quadruplexes efficiently and stably inhibit the cleavage of pre-miRNA by Dicer. Our data highlight the potential of human Dicer for binding of G-quadruplexes and allow us to propose a G-quadruplex-driven sequestration mechanism of Dicer regulation.

Funding

National Science Centre, Poland 2016/22/E/NZ1/00422 to A.K-K.

National Science Centre, Poland 2017/26/A/NZ1/01083 to J.M.B.

National Science Centre, Poland 2017/01/X/ST5/00577 to D.B

National Science Centre, Poland 2017/01/X/ST5/00589 to D.G.

the Polish Ministry of Science and Higher Education [KNOW program for years 2014-2018]

IMCB statutory funds [to J.M.B and C.N]

Poznan Supercomputing and Networking Center at the Institute of Bioorganic Chemistry, Polish Academy of Sciences computing grant 312 [to J.M.B]

Polish Grid Infrastructure computing grant rnpmc [to C. N]

Interdisciplinary Centre for Mathematical and Computational Modelling at the University of Warsaw computing grants G73-4 and GB76-30 [to C.N]