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Systematic Mapping of ADAR1 Binding Reveals its Regulatory Roles in Multiple RNA Processing Pathways [small RNA-seq]

ABSTRACT: ADARs are the primary factors underlying A-to-I editing in metazoans. We conducted the first global study of ADAR1-RNA interaction in human cells using CLIP-Seq. In contrast to the expected predominant binding of ADAR1 to Alu repeats, thousands of CLIP sites were located in non-Alu regions. This unexpectedly frequent non-Alu binding enabled discovery of transcriptome-wide functional and biophysical targets of ADAR1 in the regulation of mRNA processing including alternative 3' UTR usage and alternative splicing. In addition, a global analysis of ADAR1 binding to non-Alu regions also revealed its primary interaction with microRNA (miRNA) transcripts in the nucleus, which subsequently affected expression levels of mature miRNAs. A complex global picture was revealed regarding the dependence of this function on the double-stranded RNA binding domains or deaminase activity. Our study unfolded a broad landscape of the diverse functional roles of ADAR1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55362 | GEO | 2015/03/11

SECONDARY ACCESSION(S): PRJNA239412

REPOSITORIES: GEO

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Systematic Mapping of ADAR1 Binding Reveals its Regulatory Roles in Multiple RNA Processing Pathways [small RNA-seq]

Project description:ADARs are the primary factors underlying A-to-I editing in metazoans. We conducted the first global study of ADAR1-RNA interaction in human cells using CLIP-Seq. In contrast to the expected predominant binding of ADAR1 to Alu repeats, thousands of CLIP sites were located in non-Alu regions. This unexpectedly frequent non-Alu binding enabled discovery of transcriptome-wide functional and biophysical targets of ADAR1 in the regulation of mRNA processing including alternative 3' UTR usage and alternative splicing. In addition, a global analysis of ADAR1 binding to non-Alu regions also revealed its primary interaction with microRNA (miRNA) transcripts in the nucleus, which subsequently affected expression levels of mature miRNAs. A complex global picture was revealed regarding the dependence of this function on the double-stranded RNA binding domains or deaminase activity. Our study unfolded a broad landscape of the diverse functional roles of ADAR1. To identify ADAR binding dependent miRNA defferential expression profiles, U87MG cells were transfected with ADAR1 overexpression vector, RNA binding mutant (EAA and E912A), siRNA of ADAR1 or controls.

2015-03-11 | E-GEOD-55362 | biostudies-arrayexpress

Systematic Mapping of ADAR1 Binding Reveals its Regulatory Roles in Multiple RNA Processing Pathways [CLIP-seq]

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Project description:ADAR1 catalyzes Adenosine-to-Inosine (A-to-I) editing of double-stranded RNA and regulates global expression output through its interactions with RNA and other proteins. ADARs play important roles in development and disease, and previous work has shown that ADAR1 is oncogenic in a growing list of cancer types. Here we show that ADAR1 is important for growth and invasion in triple negative breast cancer cells, as ADAR1 loss yields reduced growth, migration & invasion, and mammosphere formation. Global RNA-seq analyses demonstrate that ADAR1 regulates both coding and non-coding targets via expression level and/or A-to-I editing. We demonstrated that a recoding edit in FLNB (chr3:58156064) inhibits the tumor suppressive activities of the protein to promote growth & invasion. We show that several tumor suppressor microRNAs are also downregulated by ADAR1 to promote cell cycle progression and invasion. This work describes several novel mechanisms of ADAR1-mediated oncogenesis in triple negative breast cancer, providing support to strategies for targeting ADAR1 in this aggressive cancer type with few treatment options.

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ADAR1 downregulation contributes to p16INK4a upregulation independent of RNA editing during senescence

Project description:Cellular senescence plays a causal role in ageing and, in mouse, depletion of p16INK4a-expressing senescent cells delays ageing-associated disorders. Adenosine deaminases acting on RNA (ADARs) RNA editing enzymes are also implicated as important regulators of human ageing and ADAR inactivation causes age-associated pathologies such as neurodegeneration in model organisms. However, the role, if any, of ADARs in cellular senescence is unknown. Here we show that ADAR1 is post-transcriptionally downregulated by autophagic degradation to promote senescence through upregulating p16INK4a. ADAR1 is downregulated during senescence post-transcriptionally by autophagy-lysosomal pathway and the downregulation is sufficient to drive senescence in both in vitro and in vivo models. Senescence induced by ADAR1 downregulation is p16INK4a dependent and independent of its RNA editing function. Mechanistically, ADAR1 promotes SIRT1 expression by affecting its RNA stability through HuR, an RNA binding protein that increases the half-life and steady state levels of its target mRNAs. And SIRT1, in turn, antagonizes translation of mRNA encoding p16INK4a. Hence, downregulation of ADAR1 and SIRT1 mediates p16INK4aupregulation by enhancing its mRNA translation. Finally, Adar1 is downregulated during ageing of mouse tissues such as brain, ovary, and intestine, and Adar1 expression correlates with Sirt1 expression in these tissues in mice. Together, our study reveals an RNA-editing independent role of ADAR1 in regulating senescence by post-transcriptionally controlling p16INK4a expression.

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ADAR1-dependent editing participates to the human beta-cells transcriptome diversity during inflammation

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Distinct interactomes of ADAR1 nuclear and cytoplasmic protein isoforms and their responses to Interferon induction

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