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Abstract
Small RNA-induced gene silencing is essential for post-transcriptional regulation of gene expression; however, it remains unclear how miRNA/siRNA efficiency is regulated. Here we show that TARBP2 is SUMOylated at K52, which can be enhanced by its phosphorylation. This modification can stabilize TARBP2 via repressing its K48-linked ubiquitination. We find that TARBP2 SUMOylation does not influence the overall production of mature miRNAs, but it regulates miRNA/siRNA efficiency. SUMOylated TARBP2 recruits Ago2 to constitute the RNA-induced silencing complex (RISC)-loading complex (RLC), and simultaneously promotes more pre-miRNAs to load into the RLC. Consequently, Ago2 is stabilized and miRNAs/siRNAs bound by TARBP2/Dicer is effectively transferred to Ago2. Thus, these processes lead to the formation of the effective RISC for RNA interference (RNAi). Collectively, our data suggest that SUMOylation of TARBP2 is required for regulating miRNA/siRNA efficiency, which is a general mechanism of miRNA/siRNA regulation.
Highlights
Small RNA-induced gene silencing is essential for post-transcriptional regulation of gene expression; it remains unclear how miRNA/short interfering RNA (siRNA) efficiency is regulated
We used the method of immunoprecipitation (IP) to confirm whether SUMO1 can be covalently conjugated to TARBP2
Flag-TARBP2 with or without GFP-SUMO1 and HA-Ubc[9] were co-transfected into 293T cells, and lysates were used for IP with anti-Flag antibody and immunoblotted with anti-GFP antibody, showing a specific band in a size of B100 kDa shifted from 50 kDa (Fig. 1b), which demonstrated that Flag-TARBP2 was conjugated with GFP-SUMO1
Summary
Small RNA-induced gene silencing is essential for post-transcriptional regulation of gene expression; it remains unclear how miRNA/siRNA efficiency is regulated. By directly binding to Dicer and PACT through the Medipal domain of the C terminal, TARBP2 can stabilize the RNA-induced silencing complex (RISC)-loading complex (RLC), which is composed of Dicer, TARBP2 and Argonaute[2] (Ago2), for miRNA processing and gene silencing[7,11,12,13,14]. Phosphorylation at Tyr[393] of Ago[2], as a key component of RISC, reduces its binding with Dicer and miRNA loading, inhibiting miRNA maturation and miRNA-guided gene silencing[20,21] These studies suggest that post-translational modifications play important roles in regulating miRNA biogenesis and RNA-induced gene silencing. We found that TARBP2 SUMOylation was linked to tumorigenesis
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