Abstract
Gene expression dictates fundamental cellular processes and its de-regulation leads to pathological conditions. A key contributor to the fine-tuning of gene expression is Dicer, an RNA-binding protein (RBPs) that forms complexes and affects transcription by acting at the post-transcriptional level via the targeting of mRNAs by Dicer-produced small non-coding RNAs. This review aims to present the contribution of Dicer protein in a wide spectrum of human pathological conditions, including cancer, neurological, autoimmune, reproductive and cardiovascular diseases, as well as viral infections. Germline mutations of Dicer have been linked to Dicer1 syndrome, a rare genetic disorder that predisposes to the development of both benign and malignant tumors, but the exact correlation of Dicer protein expression within the different cancer types is unclear, and there are contradictions in the data. Downregulation of Dicer is related to Geographic atrophy (GA), a severe eye-disease that is a leading cause of blindness in industrialized countries, as well as to psychiatric and neurological diseases such as depression and Parkinson’s disease, respectively. Both loss and upregulation of Dicer protein expression is implicated in severe autoimmune disorders, including psoriasis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis and autoimmune thyroid diseases. Loss of Dicer contributes to cardiovascular diseases and causes defective germ cell differentiation and reproductive system abnormalities in both sexes. Dicer can also act as a strong antiviral with a crucial role in RNA-based antiviral immunity. In conclusion, Dicer is an essential enzyme for the maintenance of physiology due to its pivotal role in several cellular processes, and its loss or aberrant expression contributes to the development of severe human diseases. Further exploitation is required for the development of novel, more effective Dicer-based diagnostic and therapeutic strategies, with the goal of new clinical benefits and better quality of life for patients.
Highlights
The Dicer enzyme, a well-conserved protein among eukaryotic organisms [1,2], is a large protein (~200 kDa), initially identified in Drosophila melanogaster [3]
The results show a significant reduction in Dicer expression level in patients with ankylosing spondylitis (AS) (Figure 6) and a downregulation of DGCR8 mRNA, but no effect regarding Drosha mRNA
Dicer is an essential enzyme for the maintenance of physiology due to its pivotal role in several cellular processes such as regulation of gene expression, DNA damage response, cell growth and differentiation
Summary
The Dicer enzyme, a well-conserved protein among eukaryotic organisms [1,2], is a large protein (~200 kDa), initially identified in Drosophila melanogaster [3]. Dicer main domains, ordered from the N- to the C-terminus, are helicase domain (including DExD/H, TRBP-BD and HELICc), DUF283 domain, PAZ (Piwi/Argonaute/Zwille) domain, RNase IIIa and RNase IIIb domains and dsRNA-binding domain (RBD) [9,10,12,13]. Dicer syndrome is an autosomal-dominant disease inherited in a haploinsufficient manner, recent studies have indicated the necessity of a somatic mutation in the second allele of the Dicer gene, in addition to a preexisting germline mutation in one allele (two-hit hypothesis) [37,46] These “second-hit” mutations have been found in the regions encoding the RNase III domains, which are genetic hotspots for somatic mutations within the Dicer gene [47,48]. To improve success regarding the treatment of Dicer syndrome, a functional combination of basic, translational and clinical research will be required
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