PRMT1-mediated methylation of the microprocessor-associated proteins regulates microRNA biogenesis

Abstract

MicroRNA (miRNA) biogenesis is a tightly controlled multi-step process operated in the nucleus by the activity of the Microprocessor and its associated proteins. Through high resolution mass spectrometry (MS)- proteomics we discovered that this complex is extensively methylated, with 84 methylated sites associated to 19 out of its 24 subunits. The majority of the modifications occurs on arginine (R) residues (61), leading to 81 methylation events, while 30 lysine (K)-methylation events occurs on 23 sites of the complex. Interestingly, both depletion and pharmacological inhibition of the Type-I Protein Arginine Methyltransferases (PRMTs) lead to a widespread change in the methylation state of the complex and induce global decrease of miRNA expression, as a consequence of the impairment of the pri-to-pre-miRNA processing step. In particular, we show that the reduced methylation of the Microprocessor subunit ILF3 is linked to its diminished binding to the pri-miRNAs miR-15a/16, miR-17–92, miR-301a and miR-331. Our study uncovers a previously uncharacterized role of R-methylation in the regulation of miRNA biogenesis in mammalian cells.

Curcumin inhibits the viability, migration and invasion of papillary thyroid cancer cells by regulating the miR‑301a‑3p/STAT3 axis

“…The curcumin-mediated regulation of miRNA expression, including the activation/inactivation of miRNA transcription, the regulation of associated signaling pathways and the methylation/demethylation of miRNAs, is complex ( 50 ). Spadotto et al revealed that extensive methylation of complexes led to downregulated miR-301a expression ( 51 ). Curcumin has been demonstrated to cause epigenetic modulation of miR-203 expression by demethylating the miR-203 promoter in bladder cancer ( 52 ).…”

Arginine methylation: the promise of a ‘silver bullet’ for brain tumours?

“…Similarly, MiRNA-195 reduces CARM1 expression, which is associated with decreased proliferation in colorectal cancer cells (Zheng et al 2017 ). Of note, PRMTs have recently been shown to play an important role in the regulation of miRNA synthesis (Spadotto et al 2020 ), which could open a new avenue for self-regulation of PRMT expression.…”

MicroRNAs Responding to Space Radiation

“…Drosha is a conserved protein of 160 kDa size containing two series of RNase III domains (RIIIDs) and a double stranded RNA binding domain (dsRBD) [ 9 ], which in the human body associates with DiGeorge syndrome critical region gene 8 (DGCR8) to form a microprocessor complex of 650 kDa [ 10 ]. At present, it is believed that DGCR8 can assist Drosha to identify the substrate, and the determinant of the specificity for substrate recognition is the structure of pri-miRNA [ 11 , 12 , 13 ].…”