title: Cobalt(III) Protoporphyrin Activates the DGCR8 Protein and Can Compensate microRNA Processing Deficiency.
abstract: 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.
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Barr
authors.affiliation: Interdepartmental Program in Molecular, Cellular, and Integrative Physiology, University of California, Los Angeles, CA, 90095, USA.
authors.forename: Sara H
authors.initials: SH
authors.lastname: Weitz
authors.affiliation: Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Talia
authors.initials: T
authors.lastname: Atkin
authors.affiliation: Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: PeiKen
authors.initials: P
authors.lastname: Hsu
authors.affiliation: Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Karayiorgou
authors.affiliation: Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: jag90@columbia.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Gogos
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA; Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Shimon
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: fguo@mbi.ucla.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003035:Cobalt / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D011524:Protoporphyrins / Q000737:chemistry*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification
chemical_list: D056831:Coordination Complexes; C474044:Dgcr8 protein, mouse; D035683:MicroRNAs; D011524:Protoporphyrins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D003035:Cobalt; C028025:protoporphyrin IX