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Fe(III) heme sets an activation threshold for processing distinct groups of pri-miRNAs in mammalian cells

Sara H. Weitz, Jen Quick-Cleveland, Jose P. Jacob, Ian Barr, Rachel Senturia, Kikuye Koyano, Xinshu Xiao, Shimon Weiss, Feng Guo
doi: https://doi.org/10.1101/2020.02.18.955294
Sara H. Weitz
1Interdepartmental Program in Molecular, Cellular, and Integrative Physiology, University of California, Los Angeles, California, 90095
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Jen Quick-Cleveland
2Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, 90095
8Department of Molecular Cell & Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064
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Jose P. Jacob
2Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, 90095
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Ian Barr
2Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, 90095
9Dominican University of California, San Rafael, CA 94901
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Rachel Senturia
2Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, 90095
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Kikuye Koyano
3Bioinformatics Interdepartmental Program, University of California, Los Angeles, California, 90095
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Xinshu Xiao
3Bioinformatics Interdepartmental Program, University of California, Los Angeles, California, 90095
4Department of Integrative Biology and Physiology, University of California, Los Angeles, California, 90095
7Molecular Biology Institute, University of California, Los Angeles, California, 90095
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Shimon Weiss
5Department of Chemistry and Biochemistry, University of California, Los Angeles, California, 90095
6Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California, 90095
7Molecular Biology Institute, University of California, Los Angeles, California, 90095
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Feng Guo
2Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, 90095
7Molecular Biology Institute, University of California, Los Angeles, California, 90095
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  • For correspondence: fguo@mbi.ucla.edu
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ABSTRACT

The essential biological cofactor heme is synthesized in cells in the Fe(II) form. Oxidized Fe(III) heme is specifically required for processing primary transcripts of microRNAs (pri-miRNAs) by the RNA-binding protein DGCR8, a core component of the Microprocessor complex. It is unknown how readily available Fe(III) heme is in the largely reducing environment in human cells and how changes in cellular Fe(III) heme availability alter microRNA (miRNA) expression. Here we address the first question by characterizing DGCR8 mutants with various degrees of deficiency in heme-binding. We observed a strikingly simple correlation between Fe(III) heme affinity in vitro and the Microprocessor activity in HeLa cells, with the heme affinity threshold for activation estimated to be between 0.6-5 pM under typical cell culture conditions. The threshold is strongly influenced by cellular heme synthesis and uptake. We suggest that the threshold reflects a labile Fe(III) heme pool in cells. Based on our understanding of DGCR8 mutants, we reanalyzed recently reported miRNA sequencing data and conclude that heme is generally required for processing canonical pri-miRNAs, that heme modulates the specificity of Microprocessor, and that cellular heme level and differential DGCR8 heme occupancy alter the expression of distinct groups of miRNAs in a hierarchical fashion. Overall, our study provides the first glimpse of a labile Fe(III) heme pool important for a fundamental physiological function and reveal principles governing how Fe(III) heme modulates miRNA maturation at a genomic scale. We also discuss potential states and biological significance of the labile Fe(III) heme pool.

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Posted February 19, 2020.
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Fe(III) heme sets an activation threshold for processing distinct groups of pri-miRNAs in mammalian cells
Sara H. Weitz, Jen Quick-Cleveland, Jose P. Jacob, Ian Barr, Rachel Senturia, Kikuye Koyano, Xinshu Xiao, Shimon Weiss, Feng Guo
bioRxiv 2020.02.18.955294; doi: https://doi.org/10.1101/2020.02.18.955294
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Fe(III) heme sets an activation threshold for processing distinct groups of pri-miRNAs in mammalian cells
Sara H. Weitz, Jen Quick-Cleveland, Jose P. Jacob, Ian Barr, Rachel Senturia, Kikuye Koyano, Xinshu Xiao, Shimon Weiss, Feng Guo
bioRxiv 2020.02.18.955294; doi: https://doi.org/10.1101/2020.02.18.955294

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