The Ubiquitin-specific Protease USP36 Associates with the Microprocessor Complex and Regulates miRNA Biogenesis by SUMOylating DGCR8

Abstract

MicroRNA (miRNA) biogenesis is a cellular process that produces mature miRNAs from their primary transcripts, pri-miRNAs, via two RNAse III enzyme complexes: the Drosha-DGCR8 microprocessor complex in the nucleus and the Dicer-TRBP complex in the cytoplasm. Emerging evidence suggests that miRNA biogenesis is tightly regulated by posttranscriptional and posttranslational modifications and aberrant miRNA biogenesis is associated with various human diseases including cancer. DGCR8 has been shown to be modified by SUMOylation. Yet, the SUMO ligase mediating DGCR8 SUMOylation is currently unknown. Here, we report that USP36, a nucleolar ubiquitin-specific protease essential for ribosome biogenesis, is a novel regulator of DGCR8. USP36 interacts with the microprocessor complex and promotes DGCR8 SUMOylation, specifically modified by SUMO2. USP36-mediated SUMOylation does not affect the levels of DGCR8 and the formation of the Drosha-DGCR8 complex, but promotes the binding of DGCR8 to pri-miRNAs. Consistently, abolishing DGCR8 SUMOylation significantly attenuates its binding to pri-miRNAs and knockdown of USP36 attenuates pri-miRNA processing, resulting in marked reduction of tested mature miRNAs. Induced expression of a SUMOylation-defective mutant of DGCR8 inhibits cell proliferation. Together, these results suggest that USP36 plays an important role in regulating miRNA biogenesis by SUMOylating DGCR8.

SUMOylation regulation of ribosome biogenesis: Emerging roles for USP36

“…Interestingly, we observed that USP36 strongly binds to pre-rRNA (Chen et al, 2023). The RNA-binding property of USP36 has also been shown by others wherein it binds to long noncoding RNAs (lncRNAs) (Mondal et al, 2018) and microRNAs (Treiber et al, 2017;Li et al, 2023). Indeed, it plays a role in microRNA biogenesis by binding to the microprocessor complex and mediating DGCR8 SUMOylation in the nucleolus (Li et al, 2023).…”

Cinobufotalin regulates the USP36/c-Myc axis to suppress malignant phenotypes of colon cancer cells in vitro and in vivo

“…By using Lipofectamine ® 3000 reagent (Invitrogen, MA, USA), cell transfection was carried out for 48 h as previously reported [ 42 ]. The efficiency of all transfections was examined by detecting both mRNA and protein levels with RT-PCR and western blot, respectively.…”

The Emerging Role of Ubiquitin-Specific Protease 36 (USP36) in Cancer and Beyond

“…However, it enhances the binding of DGCR8 to pri-miRNAs. Consequently, USP36 controls the processing of pri-miRNA within the nucleolus via the SUMOylation of DGCR8 [22].…”