Key Points
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Dicer is a type III cytoplasmic endoribonuclease that is involved in the maturation of several classes of small non-coding RNAs, such as microRNAs.
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Dicer is involved in the maturation of precursor microRNAs, it loads the derived small RNAs into effector Argonaute proteins, and functions as a scaffold for several interactions in the RNA interference mechanisms.
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Genetic perturbation of Dicer results in defects affecting functions ranging from embryogenesis, differentiation and homeostasis, to cancer.
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Dicer adopts an overall 'L' shape. The PAZ and Platform domains bind double-stranded RNA (dsRNA) substrate termini, the RNase III domains each cleave along the dsRNA strands, a spacer linker measures the small RNA end products, and an RNA helicase regulates its substrate recognition and activity.
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Changes in the expression of DICER1 have been associated with various cancers. In general, reduced expression is observed in many cancers, but the data are inconsistent.
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Germline loss-of-function mutations in DICER1 are associated with a pleiotropic tumour susceptibility syndrome, characterized by pleuropulmonary blastoma, cystic nephroma and other rare entities. Notably, the non-neoplastic condition multinodular goiter seems to feature prominently.
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In contrast to the loss-of-function mutations, highly specific missense mutations are found as 'second hits' in the tumours that are associated with germline mutations. These missense mutations are almost entirely limited to the RNase IIIb domain of DICER1.
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Loss-of-heterozygosity of DICER1 is rare and only seems to be frequently associated with a germline DICER1 mutation in the uncommon brain tumour pineoblastoma.
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Rare phenotypes, such as pituitary blastoma, may be particularly indicative of biallelic mutations in DICER1.
Abstract
Dicer is central to microRNA-mediated silencing and several other RNA interference phenomena that are profoundly embedded in cancer gene networks. Most recently, both germline and somatic mutations in DICER1 have been identified in diverse types of cancer. Although some of the mutations clearly reduce the dosage of this key enzyme, others dictate surprisingly specific changes in select classes of small RNAs. This Review reflects on the molecular properties of the Dicer enzymes in small RNA silencing pathways, and rationalizes the newly discovered mutations on the basis of the activities and functions of its determinants.
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Change history
10 September 2014
The copyright permission line in Figure 1c was corrected to include the copyright credit text requested by the publisher.
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Acknowledgements
The authors sincerely thank L. de Kock, N. Hamel, A. Sawh and B. Rivera for helping to compile the data shown in Figure 1a and Supplementary information S3 (figure), as well as for their artistic and conceptual contributions to Figure 1a–c. Work carried out in the authors' laboratories described in this Review has been supported by Alex's Lemonade Stand Foundation, the Canadian Cancer Society Research Institute, the Jewish General Hospital Foundation (to W.D.F), the Canadian Institute of Health Research (CIHR) MOP 86577 and the Chercheur-Boursier Salary Award J2 (to T.F.D.).
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Supplementary information
Supplementary information S1 (table)
Frequency of proven germ-line DICER1 mutations in individuals with various tumors (PDF 141 kb)
Supplementary information S2 (table)
Frequency of presumed somatic DICER1 mutations in various tumors (PDF 162 kb)
Supplementary information S3 (figure)
Germline and somatic mutations in DICER1 (including mutations not confirmed to be somatic in origin) Compare to Fig 1A in main paper, which indicates sites only of mutations proven to be somatic. (PDF 1151 kb)
Glossary
- Small RNAs
-
Includes all classes of small non-coding RNAs, small interfering RNAs (siRNAs), endogenous siRNAs (endo-siRNAs), microRNAs, and PIWI-interacting RNAs (piRNAs).
- MicroRNAs
-
(miRNAs). Small RNAs that are derived from genome-encoded hairpins, acting in trans on mRNA translation and stability. Canonical biogenesis involves Dicer, although alternative pathways have been described.
- Long dsRNA substrates
-
A generic term that is used to describe exogenous Dicer substrates such as virus RNA genomes, or experimentally-introduced double-stranded RNA (dsRNA).
- Small interfering RNAs
-
(siRNAs). Small RNAs that are derived from long double-stranded substrates, usually involve full base-pairing with mRNA targets and a mode of action through Argonaute slicer activity. siRNAs can be genome-encoded (endogenous siRNAs) or from exogenous sources (viruses or experimental use of siRNA).
- Endogenous siRNAs
-
(Endo-siRNAs). Small interfering RNAs (siRNAs) that are derived from endogenous genomic loci. This term is often used to describe small RNAs derived from repetitive and transposable elements. Endo-siRNAs can function in cis (on the locus encoding the trigger itself) or in trans by targeting repeated genomic sequences.
- Pulmonary mesenchyme
-
The respiratory epithelium of the lung is surrounded by mesenchyme, derived from the mesoderm embryonic layer and from which several cell types can arise: smooth muscle, pericytes, lipocytes and fibroblasts. It is from mesenchyme that DICER1-related pleuropulmonary blastoma (PPB) is believed to arise.
- Cystic nephroma
-
These tumours are comprised of liquid-filled cysts, often multi-locular in nature. They do not contain any renal parenchyma and are lined by a simple epithelium that has a so-called 'hobnail' appearance. The stroma usually has a spindle-cell morphology. Although they can overtake functioning renal tissue, malignant transformation (to sarcoma) is rare but has been observed in DICER1 mutation carriers.
- Dysontogenic
-
A process by which embryonic differentiation is perturbed but does not result in neoplasia.
- Pulmonary sequestration
-
Occurs when a section of the developing lung is not connected to the respiratory (bronchial) tree. There are two types — intralobar and extralobar, depending on whether the sequestered lobes are within or external to the main, functioning part of the lung. The blood supply for both types of sequestration is separate to the normal lung. Importantly, 50% of pulmonary sequestrations are accompanied by cystic dysplasias that are distinct from the cysts of pleuropulmonary blastoma (PPB).
- Botryoides
-
This descriptive term is from the Greek, meaning 'taking the form of a bunch of grapes'; they are sarcomatous multi-polyp clusters occurring in hollow organs lined by mucus membrane, such as sinuses, nasopharynx, pulmonary cysts, bladder, cervix, vagina and uterus.
- Phthisis bulbi
-
Phthisis is a Latin word, derived from the Greek phthinein (to waste away). Bulbi refers to the globe of the eye. This term is a general one, applied to any destructive process resulting in a non-functional and usually shrunken eye. When it is present at birth, it is referred to as congenital phthisis bulbi.
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Foulkes, W., Priest, J. & Duchaine, T. DICER1: mutations, microRNAs and mechanisms. Nat Rev Cancer 14, 662–672 (2014). https://doi.org/10.1038/nrc3802
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DOI: https://doi.org/10.1038/nrc3802
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