TY - JOUR
T1 - Heme enables proper positioning of Drosha and DGCR8 on primary microRNAs
AU - Partin, Alexander C.
AU - Ngo, Tri D.
AU - Herrell, Emily
AU - Jeong, Byung Cheon
AU - Hon, Gary
AU - Nam, Yunsun
N1 - Funding Information:
We thank support from the Cecil H. and Ida Green Center Training Program in Reproductive Biology Sciences Research. We appreciate help from Chad Brautigam at the Macromolecular Biophysics Resource at UT Southwestern for AUC experiments. We thank the McDermott Center at UT Southwestern for assistance with capillary electrophoresis. We appreciate helpful comments on the manuscript from Kim Orth and Yuh Min Chook. Y.N. is a Southwestern Medical Foundation Scholar in Biomedical Research (Endowed Scholar Program at UT Southwestern), a Pew Scholar in the Biomedical Sciences, and a Packard Fellow (2013-39275). This study was supported by grants from the Welch Foundation (I-1851), Cancer Prevention Research Institute of Texas (R1221), American Cancer Society/the Harold C. Simmons Comprehensive Cancer Center (ACS-IRG-02-196), and NIH/NIGMS (5R01GM122960).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - MicroRNAs regulate the expression of many proteins and require specific maturation steps. Primary microRNA transcripts (pri-miRs) are cleaved by Microprocessor, a complex containing the RNase Drosha and its partner protein, DGCR8. Although DGCR8 is known to bind heme, the molecular role of heme in pri-miR processing is unknown. Here we show that heme is critical for Microprocessor to process pri-miRs with high fidelity. Furthermore, the degree of inherent heme dependence varies for different pri-miRs. Heme-dependent pri-miRs fail to properly recruit Drosha, but heme-bound DGCR8 can correct erroneous binding events. Rather than changing the oligomerization state, heme induces a conformational change in DGCR8. Finally, we demonstrate that heme activates DGCR8 to recognize pri-miRs by specifically binding the terminal loop near the 3′ single-stranded segment.
AB - MicroRNAs regulate the expression of many proteins and require specific maturation steps. Primary microRNA transcripts (pri-miRs) are cleaved by Microprocessor, a complex containing the RNase Drosha and its partner protein, DGCR8. Although DGCR8 is known to bind heme, the molecular role of heme in pri-miR processing is unknown. Here we show that heme is critical for Microprocessor to process pri-miRs with high fidelity. Furthermore, the degree of inherent heme dependence varies for different pri-miRs. Heme-dependent pri-miRs fail to properly recruit Drosha, but heme-bound DGCR8 can correct erroneous binding events. Rather than changing the oligomerization state, heme induces a conformational change in DGCR8. Finally, we demonstrate that heme activates DGCR8 to recognize pri-miRs by specifically binding the terminal loop near the 3′ single-stranded segment.
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U2 - 10.1038/s41467-017-01713-y
DO - 10.1038/s41467-017-01713-y
M3 - Article
C2 - 29170488
AN - SCOPUS:85034848570
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1737
ER -