Dicing the Disease with Dicer: The Implications of Dicer Ribonuclease in Human Pathologies

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.

Gene of the month:DICER1:ruler and controller

“…13 Erroneous expression of DICER1 has also been associated with autoimmune disorders with both loss and upregulation contributing to a range of pathologies including ankylosing spondylitis, psoriasis, rheumatoid arthritis, multiple sclerosis and autoimmune thyroid disorders. 14 Potentially more subtle effects of timing and extent of gene expression during embryogenesis could contribute to human facial variation as, in a study by Liu et al, SNP rs7161418 in DICER1 was one of 12 SNPS from 10 genes significantly associated with facial morphology in the Han Chinese populations. 15 Ageing is associated with decreased expression of DICER1 and changes in its diurnal expression pattern.…”

Circulating microRNAs and Clinicopathological Findings of Papillary Thyroid Cancer: A Systematic Review

“…It has been found that when DICER1 gene is mutated, through inherited or acquired mutation, patients develop an increased predisposition to thyroid tumor development. Patients with germline inherited DICER1 loss-of-function mutations could suffer from a wide variety of rare life-threatening childhoodonset malignancies, such as benign and malignant thyroid neoplasms including PTC, collectively called DICER1 syndrome (75). Also, acquired somatic mutations or downregulation of DICER1 expression have been found in earlyadulthood-onset well differentiated thyroid cancer (PTC and follicular thyroid cancer) and poorly differentiated thyroid carcinoma.…”

Emerging concepts in the treatment of optic neuritis: mesenchymal stem cell-derived extracellular vesicles

“…MicroRNA appears to mediate most EV effects [ 159 ] by three known mechanisms: [ 1 ] Binding the 3’UTR of their target mRNA, silencing the gene and blocking translation, [ 2 ] Translational repression by cleaving and degrading mRNA, [ 3 ] De-adenylation and degradation of mRNAs [ 160 ]. The miRNA processing endonuclease Dicer is a member of the ribonuclease III family that functions in the RNA interference pathway to cleave long double stranded RNA molecules into small RNAs including miRNA and siRNA [ 161 , 162 ]. Dicer1 is essential to the miRNA pathway and Dicer2 facilitates the siRNA pathway [ 161 ].…”

“…Dicer1 is essential to the miRNA pathway and Dicer2 facilitates the siRNA pathway [ 161 ]. Dicer cleaves the precursor miRNA (pre-miRNA) hairpins at the stem-loop boundary, generating mature miRNA [ 162 ]. ADicer knockout mice (ADicerKO) lack effective miRNA processing in adipose tissue.…”