The Zalpha domain from human ADAR1 binds to the Z-DNA conformer of many different sequences

Herbert, Alan; Schade, Markus; Lowenhaupt, Ky; Alfken, Jens; Schwartz, Thomas; Shlyakhtenko, Luda S.; Lyubchenko, Yuri L.; Rich, Alexander

doi:10.1093/nar/26.15.3486

Cited by 107 publications

(112 citation statements)

References 40 publications

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“…While the effects of ADAR1 on miRNA processing, expression, and thereby functions were independent of RNA editing, they did depend on RNA-binding capacity. We show that both the dsRBD, essential for binding to the target RNA molecule and/or other RNA-binding proteins (51), and the Z-DBD, necessary for ADAR1 effects on NF-90 activity (30), nuclear export, and binding to specific sequences based on their conformation (52,53), are required. ADAR1 truncation mutants lacking the dsRBD or ZDBD failed to exert any impact either on cellular proliferation or miRNA biogenesis (Figures 3 and 5).…”

Section: Discussionmentioning

confidence: 97%

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: Discussionmentioning

confidence: 97%

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

et al. 2013

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“…The mean of six data accumulations was smoothed with a third order polynomial function. A positive control of d(CG) oligomers in the Z conformation at high ionic strength (4 M NaCl) is shown elsewhere [10].…”

Section: Spectroscopymentioning

confidence: 99%

A 6 bp Z‐DNA hairpin binds two Zα domains from the human RNA editing enzyme ADAR1

et al. 1999

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The ZK K domain of the human RNA editing enzyme double-stranded RNA deaminase I (ADAR1) binds to lefthanded Z-DNA with high affinity. We found by analytical ultracentrifugation and CD spectroscopy that two ZK K domains bind to one d(CG) 3 T 4 (CG) 3 hairpin which contains a stem of six base pairs in the Z-DNA conformation. Both wild-type ZK K and a C125S mutant show a mean dissociation constant of 30 nM as measured by surface plasmon resonance and analytical ultracentrifugation. Our data suggest that short (v v 6 bp) segments of Z-DNA within a gene are able to recruit two ADAR1 enzymes to that particular site.z 1999 Federation of European Biochemical Societies.

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“…We and others have previously used SFM to analyze protein-nucleic acid interactions; for example, Hansma et al (1999) performed a functional analysis of polymerases on their respective templates by SFM; Herbert et al (1998) showed that the z-␣ domain of ADAR1 binds to Z-DNA; Kasas et al (1997) were able to monitor the dynamics of Escherichia coli RNA polymerase in the SFM; and we (Bonin et al 2000) have determined preferential binding sites of a protein on dsRNA.…”

Section: Introductionmentioning

confidence: 99%

Biochemical analysis and scanning force microscopy reveal productive and nonproductive ADAR2 binding to RNA substrates

Klaue

Källman²,

Bonin³

et al. 2003

RNA

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Scanning force microscopy (SFM) can be used to image biomolecules at high resolution. Here we demonstrate that singlemolecule analysis by SFM complements biochemical data on RNA protein binding and can provide information that cannot be obtained by the usual biochemical methods. We have used this method to study the interaction between the RNA editing enzyme ADAR2 and RNA transcripts containing selective and nonselective editing sites. The natural selectively edited R/G site from glutamate receptor subunit B (GluR-B) was inserted into an RNA backbone molecule consisting of a completely doublestranded (ds) central part and incompletely paired ends derived from potato spindle tuber viroid (PSTVd). This molecule was efficiently edited at the R/G site, but promiscuous editing occurred at nonselective sites in the completely double-stranded region. The construct was also used to analyze binding of ADAR2 to wild-type and modified R/G editing sites in relation to binding at other nonselectively edited sites. Editing analysis together with SFM allow us to differentiate between binding and enzymatic activity. ADAR2 has been reported to have a general affinity to dsRNA. However, we show that there is a prominent bias for stable binding at sites selectively edited over other edited sites. On the other hand, promiscuous editing at nonselective sites apparently results from transient binding of the enzyme to the substrate. Furthermore, we find distinct sites with nonproductive binding of the enzyme.

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The Zalpha domain from human ADAR1 binds to the Z-DNA conformer of many different sequences

Cited by 107 publications

References 40 publications

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

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

A 6 bp Z‐DNA hairpin binds two Zα domains from the human RNA editing enzyme ADAR1

Biochemical analysis and scanning force microscopy reveal productive and nonproductive ADAR2 binding to RNA substrates

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