Essential role of the amino-terminal region of Drosha for the Microprocessor function

Amit Prabhakar; Song Hu; Jin Tang; Prajakta Ghatpande; Giorgio Lagna; Xuan Jiang; Akiko Hata

doi:10.1016/j.isci.2023.107971

Essential role of the amino-terminal region of Drosha for the Microprocessor function

iScience. 2023 Sep 20;26(10):107971. doi: 10.1016/j.isci.2023.107971. eCollection 2023 Oct 20.

Authors

Amit Prabhakar¹, Song Hu², Jin Tang², Prajakta Ghatpande¹, Giorgio Lagna^{1

3}, Xuan Jiang^{1

2}, Akiko Hata^{1

4}

Affiliations

¹ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
² Molecular Cancer Research Center, Sun Yat-Sen University School of Medicine, Guangzhou 511400, P.R.China.
³ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94143, USA.

Abstract

Drosha is a core component of the Microprocessor complex that cleaves primary-microRNAs (pri-miRNAs) to generate precursor-miRNA and regulates the expression of ∼80 ribosomal protein (RP) genes. Despite the fact that mutations in the amino-terminal region of Drosha (Drosha-NTR) are associated with a vascular disorder, hereditary hemorrhagic telangiectasia, the precise function of Drosha-NTR remains unclear. By deleting exon 5 from the Drosha gene and generating a Drosha mutant lacking the NTR (ΔN), we demonstrate that ΔN is unable to process pri-miRNAs, which leads to a global miRNA depletion, except for the miR-183/96/182 cluster. We find that Argonaute 2 facilitates the processing of the pri-miR-183/96/182 in ΔN cells. Unlike full-length Drosha, ΔN is not degraded under serum starvation, resulting in unregulated RP biogenesis and protein synthesis in ΔN cells, allowing them to evade growth arrest. This study reveals the essential role of Drosha-NTR in miRNA production and nutrient-dependent translational control.

Keywords: Molecular biology; Omics.

Grants and funding

R01 HL153915/HL/NHLBI NIH HHS/United States