Cobalt(III) Protoporphyrin Activates the DGCR8 Protein and Can Compensate microRNA Processing Deficiency

Ian Barr, Sara H. Weitz, Talia Atkin, Peiken Hsu, Maria Karayiorgou, Joseph A. Gogos*, Shimon Weiss, Feng Guo

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Summary Processing of microRNA primary transcripts (pri-miRNAs) is highly regulated and defects in the processing machinery play a key role in many human diseases. In 22q11.2 deletion syndrome (22q11.2DS), heterozygous deletion of DiGeorge critical region gene 8 (DGCR8) causes a processing deficiency, which contributes to abnormal brain development. The DGCR8 protein is the RNA-binding partner of Drosha RNase, both essential for processing canonical pri-miRNAs. To identify an agent that can compensate reduced DGCR8 expression, we screened for metalloporphyrins that can mimic the natural DGCR8 heme cofactor. We found that Co(III) protoporphyrin IX (PPIX) stably binds DGCR8 and activates it for pri-miRNA processing in vitro and in HeLa cells. Importantly, treating cultured Dgcr8+/- mouse neurons with Co(III)PPIX can compensate the pri-miRNA processing defects. Co(III)PPIX is effective at concentrations as low as 0.2 μM and is not degraded by heme degradation enzymes, making it useful as a research tool and a potential therapeutic.

Original languageEnglish (US)
Pages (from-to)793-802
Number of pages10
JournalChemistry and Biology
Volume22
Issue number6
DOIs
StatePublished - Jun 20 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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    Barr, I., Weitz, S. H., Atkin, T., Hsu, P., Karayiorgou, M., Gogos, J. A., Weiss, S., & Guo, F. (2015). Cobalt(III) Protoporphyrin Activates the DGCR8 Protein and Can Compensate microRNA Processing Deficiency. Chemistry and Biology, 22(6), 793-802. https://doi.org/10.1016/j.chembiol.2015.05.015