Heme enables proper positioning of Drosha and DGCR8 on primary microRNAs

Area of Science:

• Molecular Biology
• Biochemistry
• Genetics

Background:

• MicroRNAs (miRNAs) are key regulators of gene expression.
• Primary miRNAs (pri-miRs) undergo processing by the Microprocessor complex, comprising Drosha and DGCR8.
• The role of heme, a known DGCR8 ligand, in pri-miR processing remained unclear.

Purpose of the Study:

• To elucidate the molecular function of heme in the Microprocessor complex.
• To investigate how heme influences pri-miR processing fidelity.
• To understand the mechanism of heme-mediated DGCR8 activation.

Main Methods:

• Biochemical assays to assess pri-miR processing efficiency.
• Protein-RNA binding studies to analyze Drosha and DGCR8 interactions.
• Structural analysis (e.g., conformational changes) of DGCR8 upon heme binding.

Main Results:

• Heme is critical for high-fidelity processing of pri-miRs by the Microprocessor complex.
• The dependence on heme varies among different pri-miRs.
• Heme binding to DGCR8 corrects misrecruitment of Drosha to pri-miRs.
• Heme induces a conformational change in DGCR8, not altering its oligomerization state.
• Heme-activated DGCR8 specifically binds the terminal loop of pri-miRs.

Conclusions:

• Heme acts as a crucial cofactor for DGCR8, enhancing Microprocessor activity and specificity.
• Heme binding stabilizes DGCR8 conformation, leading to accurate Drosha recruitment and pri-miR processing.
• This study reveals a novel regulatory mechanism for microRNA biogenesis involving heme-mediated protein activation.