Article abstract

Nature Structural & Molecular Biology 14, 23 - 29 (2007)
Published online: 10 December 2006 | Corrected online: 6 October 2008 | doi:10.1038/nsmb1182



There is an Addendum (October 2008) associated with this Article.

Heme is involved in microRNA processing

Michael Faller1, Michio Matsunaga1, Sheng Yin2, Joseph A Loo1,2 & Feng Guo1

MicroRNAs (miRNAs) regulate the expression of a large number of protein-coding genes. Their primary transcripts (pri-miRNAs) have to undergo multiple processing steps to reach the functional form. Little is known about how the processing of miRNAs is modulated. Here we show that the RNA-binding protein DiGeorge critical region-8 (DGCR8), which is essential for the first processing step, is a heme-binding protein. The association with heme promotes dimerization of DGCR8. The heme-bound DGCR8 dimer seems to trimerize upon binding pri-miRNAs and is active in triggering pri-miRNA cleavage, whereas the heme-free monomer is much less active. A heme-binding region of DGCR8 inhibits the pri-miRNA–processing activity of the monomer. This putative autoinhibition is overcome by heme. Our finding that heme is involved in pri-miRNA processing suggests that the gene-regulation network of miRNAs and signal-transduction pathways involving heme might be connected.

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  1. Department of Biological Chemistry, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California 90095, USA.
  2. Department of Chemistry and Biochemistry, Molecular Biology Institute, University of California at Los Angeles (UCLA), Los Angeles, California 90095, USA.

Correspondence to: Feng Guo1 e-mail: fguo@mbi.ucla.edu

* Here we report that the calibration peaks of size-exclusion chromatography (SEC) were misassigned in our paper. The estimated molecular weights based on the new calibration curve are larger than those reported (see PDF for details). However, our conclusions about oligomerization states of the heme-bound and heme-free NC1 and the NC9 proteins are supported by additional experimental evidence, and are unchanged. The heme-bound NC1 is a dimer, as was directly confirmed using ESI MS. NC9 and the heme-free NC1 are largely monomeric, as indicated by our unpublished ESI mass spectra. In addition, NC9 is similar to the monomeric DGCR8 core, as demonstrated by its crystal structure (Nat. Struct. Mol. Biol. 14, 847–853, 2007). In our paper, we proposed a cooperative trimer model in which the heme-free NC1 dimer, as well as NC9, further trimerizes upon association with the pri-miR-30a RNA. This model is supported by the new SEC estimates. Therefore, SEC seems to systematically overestimate the molecular weights of DGCR8 proteins and protein–RNA complexes, probably due to their elongated shapes. The new estimated molecular weight of the heme-free NC1 in complex with pri-miR-30a is consistent with a model in which three heme-free NC1 molecules associate with one pri-miRNA, but this estimate is not conclusive. Further corroboration on the oligomerization state of the heme-free NC1 upon binding to pri-miRNAs is needed.

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