The kinase ABL phosphorylates the microprocessor subunit DGCR8 to stimulate primary microRNA processing in response to DNA damage

DNA damage triggers the biogenesis of some miRNAs through the activity of the kinase ABL. EnABLing DNA damage–induced miRNA production DNA damage stimulates the production of microRNAs (miRNAs) that help coordinate DNA damage repair, cell cycle checkpoints, and apoptosis. Here, Tu et al. found that the tyrosine kinase ABL directly activated the production of a subset of DNA damage–induced miRNAs, particularly miR-34c. ABL phosphorylated the RNA binding protein DGCR8, which binds the enzyme Drosha to form the miRNA processing complex. Mutating the phosphorylation site in DGCR8 impaired the recruitment of Drosha to immature miR-34c and its subsequent processing in cultured cells, whereas expressing a nuclear import–defective mutant of ABL in mice reduced the abundance of miR-34c as well as apoptosis in kidney epithelial cells exposed to the DNA-damaging agent cisplatin. These results suggest that ABL coordinates aspects of the DNA damage response by promoting the production of some miRNAs. The DNA damage response network stimulates microRNA (miRNA) biogenesis to coordinate repair, cell cycle checkpoints, and apoptosis. The multistep process of miRNA biogenesis involves the cleavage of primary miRNAs by the microprocessor complex composed of the ribonuclease Drosha and the RNA binding protein DGCR8. We found that the tyrosine kinase ABL phosphorylated DGCR8, a modification that was required for the induction of a subset of miRNAs after DNA damage. Focusing on the miR-34 family, ABL stimulated the production of miR-34c, but not miR-34a, through Drosha/DGCR8-dependent processing of primary miR-34c (pri-miR-34c). This miRNA-selective effect of ABL required the sequences flanking the precursor miR-34c (pre-miR-34c) stem-loop. In pri-miRNA processing, DGCR8 binds the pre-miR stem-loop and recruits Drosha to the miRNA. RNA cross-linking assays showed that DGCR8 and Drosha interacted with pri-miR-34c, but we found an inverse correlation between ABL-stimulated processing and DGCR8 association with pri-miR-34c. When coexpressed in HEK293T cells, ABL phosphorylated DGCR8 at Tyr267. Ectopic expression of a Y267F-DGCR8 mutant reduced the recruitment of Drosha to pri-miR-34c and prevented ABL or Drosha from stimulating the processing of pri-miR-34c. In mice engineered to express a nuclear import–defective mutant of ABL, miR-34c, but not miR-34a, expression was reduced in the kidney, and apoptosis of the renal epithelial cells was impaired in response to cisplatin. These results reveal a new pathway in the DNA damage response wherein ABL-dependent tyrosine phosphorylation of DGCR8 stimulates the processing of selective primary miRNAs.