Modulation of MicroRNA Expression and Function by ADARs

Wulff, Bjorn-Erik; Nishikura, Kazuko

doi:10.1007/82_2011_151

Cited by 24 publications

(21 citation statements)

References 37 publications

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“…ADAR1 alters the expression of many miRNAs (Supplemental Table 3), which might shape the metastatic phenotype. It was previously shown that RNA editing of specific primiRNA transcripts by ADAR1 affects their biogenesis (11). Here, we hypothesized that ADAR1 regulates miRNA biogenesis independently of RNA editing.…”

Section: Adar1 Controls Cancer Features By Regulation Of Mirna Expresmentioning

confidence: 89%

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MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth

et al. 2013

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Some solid tumors have reduced posttranscriptional RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes, but the functional significance of this alteration has been unclear. Here, we found the primary RNA-editing enzyme ADAR1 is frequently reduced in metastatic melanomas. In situ analysis of melanoma samples using progression tissue microarrays indicated a substantial downregulation of ADAR1 during the metastatic transition. Further, ADAR1 knockdown altered cell morphology, promoted in vitro proliferation, and markedly enhanced the tumorigenicity in vivo. A comparative whole genome expression microarray analysis revealed that ADAR1 controls the expression of more than 100 microRNAs (miRNAs) that regulate many genes associated with the observed phenotypes. Importantly, we discovered that ADAR1 fundamentally regulates miRNA processing in an RNA binding-dependent, yet RNA editing-independent manner by regulating Dicer expression at the translational level via let-7. In addition, ADAR1 formed a complex with DGCR8 that was mutually exclusive with the DGCR8-Drosha complex that processes pri-miRNAs in the nucleus. We found that cancer cells silence ADAR1 by overexpressing miR-17 and miR-432, which both directly target the ADAR1 transcript. We further demonstrated that the genes encoding miR-17 and miR-432 are frequently amplified in melanoma and that aberrant hypomethylation of the imprinted DLK1-DIO3 region in chromosome 14 can also drive miR-432 overexpression.

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Section: Adar1 Controls Cancer Features By Regulation Of Mirna Expresmentioning

confidence: 89%

“…In addition, editing of regulatory RNAs (pri-and pre-mi RNAs) by ADAR1 has been reported (11). Editing of primiRNAs by ADAR1 may interfere with miRNA biogenesis at the precursor stage and thereby alter their homeostasis in the cell (12) or target binding (13).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth

et al. 2013

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“…ADAR editing activity has the potential to alter mRNA coding potential, affect alternative splicing, and influence miRNA biogenesis and targeting (Hundley and Bass 2010;Rieder and Reenan 2012;Rosenthal and Seeburg 2012;Wulff and Nishikura 2012). Moreover, the editing levels of individual sites can vary considerably during development and rarely reach 100% editing efficiency demonstrating the dynamic effect of ADARs on the transcriptome (Wahlstedt et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Trans and cis factors affecting A-to-I RNA editing efficiency of a noncoding editing target in C. elegans

Washburn

Hundley

2016

RNA

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Adenosine-to-inosine RNA editing by ADARs affects thousands of adenosines in an organism's transcriptome. However, adenosines are not edited at equal levels nor do these editing levels correlate well with ADAR expression levels. Therefore, additional mechanisms are utilized by the cell to dictate the editing efficiency at a given adenosine. To examine cis-and transacting factors that regulate A-to-I editing levels specifically in neural cells, we utilized the model organism Caenorhabditis elegans. We demonstrate that a double-stranded RNA (dsRNA) binding protein, ADR-1, inhibits editing in neurons, which is largely masked when examining editing levels from whole animals. Furthermore, expression of ADR-1 and mRNA expression of the editing target can act synergistically to regulate editing efficiency. In addition, we identify a dsRNA region within the Y75B8A.8 3 ′ UTR that acts as a cis-regulatory element by enhancing ADR-2 editing efficiency. Together, this work identifies mechanisms that regulate editing efficiency of noncoding A-to-I editing sites, which comprise the largest class of ADAR targets.

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“…Adenosine-to-inosine editing of pri-miRNAs can lead to changes in miRNA stability or alter their target selection [ 108 ]. Editing can also change the target specifi city of the miRNA if it occurs in miRNA sequences [ 108 ].…”

Section: Regulation Of the Cropping Dicing And Slicing Eventsmentioning

confidence: 99%

Biogenesis and Physiology of MicroRNAs

Melo

2013

Non-Coding RNAs and Cancer

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MicroRNAs (miRNAs) are small noncoding RNAs 17-25 nucleotides long that control gene expression by promoting degradation or repressing translation of target mRNAs. Since each miRNA regulates the expression of hundreds of target mRNAs, miRNAs can be seen as master-coordinators, effi ciently regulating fundamental cellular processes such as proliferation, apoptosis, and development. MiRNAs are synthesized in the cell through a multistep coordinated process that starts in the nucleus and proceeds to the cytoplasm culminating with the production of the biological active form, the miRNA. This maturation process consists of a series of biochemical steps that convert the primary miRNA transcript into an intermediate precursor miRNA hairpin and culminates with the formation of the mature miRNA. The spatiotemporal control of miRNA abundance is made possible, in part, by the regulation of its biosynthesis pathway, where alterations can lead to global miRNA deregulation. Since miRNAs are involved in a broad range of developmental and physiological processes their deregulation appears to play a fundamental role in the onset, progression, and dissemination of many cancers as well as in many other human diseases.

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Modulation of MicroRNA Expression and Function by ADARs

Cited by 24 publications

References 37 publications

MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth

MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth

Trans and cis factors affecting A-to-I RNA editing efficiency of a noncoding editing target in C. elegans

Biogenesis and Physiology of MicroRNAs

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