EnABLing microprocessor for apoptosis

Abstract

The Microprocessor complex consisting of DROSHA (a type III ribonuclease) and DGCR8 (DiGeorge syndrome critical region gene 8-encoded RNA binding protein) recognizes and cleaves the precursor microRNA hairpin (pre-miRNA) from the primary microRNA transcript (pri-miRNA). The Abelson tyrosine kinase 1 (ABL) phosphorylates DGCR8 to stimulate the cleavage of a subset of pro-apoptotic pri-miRNAs, thus expanding the nuclear functions of ABL to include regulation of RNA processing.

Keywords: ABL; BCR-ABL; DGC; DNA damage response; DROSHA; R8; tyrosine phosphorylation.

Figure 1.

ABL phosphorylates DGCR8 to stimulate production of pro-apoptotic microRNAs. Sequences flanking the precursor microRNA hairpin of primary microRNA-34c (depicted as red lines) are inhibitory for processing. In the cis-regulation model, these flanking sequences interact with DGCR8 (DiGeorge syndrome critical region gene 8-encoded RNA binding protein, a subunit of microprocessor) to generate a non-productive complex that cannot interact with DROSHA (a type III ribonuclease, also a subunit of Microprocessor). In the trans-regulation model, these flanking sequences recruit another RNA binding protein (RBPX) that binds DGCR8 in place of DROSHA. The Abelson tyrosine kinase 1 (ABL) overrides the inhibitory effects of these flanking sequences by phosphorylating DGCR8 on tyrosine-267. In the cis-regulation model, tyrosine phosphorylation converts the non-productive complex into a productive DGCR8-DROSHA complex. In the trans-regulation model, tyrosine phosphorylation disrupts the DGCR8 interaction with RBPX to make room for DROSHA. ABL is required for processing of a subset of primary microRNAs that have been shown to have pro-apoptotic functions.