Cobalt(III) protoporphyrin activates the DGCR8 protein and can compensate microRNA processing deficiency

dc.contributor.authorBarr, Ian
dc.contributor.authorWeitz, Sara H.
dc.contributor.authorAtkin, Talia
dc.contributor.authorHsu, PeiKen
dc.contributor.authorKarayiorgou, Maria
dc.contributor.authorGogos, Joseph A.
dc.contributor.authorWeiss, Shimon
dc.contributor.authorGuo, Feng
dc.date.accessioned2016-09-19T08:32:59Z
dc.date.available2016-09-19T08:32:59Z
dc.date.issued2015-06-18
dc.description.abstractProcessing 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 ribonuclease, 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.en_ZA
dc.description.departmentPsychiatryen_ZA
dc.description.librarianam2016en_ZA
dc.description.sponsorshipNational Institutes of Health Grants GM080563 (to F.G.), MH67068 (M.K. and J.A.G.), MH077235 (J.A.G.), T32GM008496 (S.H.W.). S.H.W. and I.B. were supported by UCLA Dissertation Year Fellowships. S.W. acknowledges support from Willard Chair funds.en_ZA
dc.description.urihttp://www.journals.elsevier.com/chemistry-and-biologyen_ZA
dc.identifier.citationBarr, I, Weitz, SH, Atkin, T, Hsu, P, Karayiorgou, M, Gogos, JA, Weiss, S & Guo, F 2015, 'Cobalt(III) protoporphyrin activates the DGCR8 protein and can compensate microRNA processing deficiency', Chemistry and Biology, vol. 22, no. 6, pp. 793-802.en_ZA
dc.identifier.issn1074-5521 (print)
dc.identifier.issn1879-1301 (online)
dc.identifier.other10.1016/j.chembiol.2015.05.015
dc.identifier.urihttp://hdl.handle.net/2263/56742
dc.language.isoenen_ZA
dc.publisherElsevieren_ZA
dc.rights© 2015 Elsevier Ltd. All rights reserved. Notice : this is the author’s version of a work that was accepted for publication in Chemistry and Biology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. A definitive version was subsequently published in Chemistry and Biology, vol. 22, no. 3, pp. 793-802, 2015. doi : 10.1016/j.chembiol.2015.05.015.en_ZA
dc.subjectHeLa cellsen_ZA
dc.subjectCo(III)PPIXen_ZA
dc.subjectIn vitroen_ZA
dc.subjectProteinen_ZA
dc.titleCobalt(III) protoporphyrin activates the DGCR8 protein and can compensate microRNA processing deficiencyen_ZA
dc.typePostprint Articleen_ZA

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