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

doi:10.1016/j.chembiol.2015.05.015

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

University of California at Los Angeles
Columbia University

Research output: Contribution to journal › Article › peer-review

11 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 language	English
Pages (from-to)	793-802
Number of pages	10
Journal	Chemistry and Biology
Volume	22
Issue number	6
DOIs	https://doi.org/10.1016/j.chembiol.2015.05.015
State	Published - 18 Jun 2015
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Ltd All rights reserved.

Funding

We thank J. Valentine and K. Barnese for use of the anaerobic chamber and J. Feigon for use of spectrophotometer. This project was supported by NIH 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.

Funders	Funder number
National Institutes of Health	GM080563, MH67068, MH077235
National Institute of General Medical Sciences	T32GM008496
University of California, Los Angeles

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1016/j.chembiol.2015.05.015

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title = "Cobalt(III) Protoporphyrin Activates the DGCR8 Protein and Can Compensate microRNA Processing Deficiency",

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.",

author = "Ian Barr and Weitz, \{Sara H.\} and Talia Atkin and Peiken Hsu and Maria Karayiorgou and Gogos, \{Joseph A.\} and Shimon Weiss and Feng Guo",

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AU - Barr, Ian

AU - Weitz, Sara H.

AU - Atkin, Talia

AU - Hsu, Peiken

AU - Karayiorgou, Maria

AU - Gogos, Joseph A.

AU - Weiss, Shimon

AU - Guo, Feng

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Funding

UN SDGs

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