Journal Article

DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome

Avşar Ilık, İbrahim, Manke, Thomas, Pessoa Rodrigues, Cecilia, Maticzka, Daniel, Akhtar, Asifa, Bhardwaj, Vivek, Aktaş, Tuğçe, Backofen, Rolf, Mittler, Gerhard

2017

Overview

In the absence of DHX9, circular RNAs accumulate and transcription and translation are dysregulated—effects that are exacerbated by concomitant depletion of the RNA-editing enzyme ADAR. DHX9 suppresses Alu-derived defects In the human genome, there are more than a million copies of the Alu transposable element. Movement of Alu elements is a common source of mutations, but as insertions usually occur in non-coding regions, they are often without discernible effect. Alu elements located near one another in an inverted orientation will form secondary structures that may affect various nuclear processes. Asifa Akhtar and colleagues find that the RNA helicase, DHX9, binds transcribed ‘IRAlus’ (inverted repeat Alu elements). In the absence of DHX9, circular RNAs accumulate, and transcription and translation are dysregulated. These effects are further exacerbated by co-depletion of DHX9 and ADAR p150, an interferon-inducible RNA modification enzyme. The authors conclude that these proteins protect against transposon insertion, which can have deleterious effects on gene expression. Transposable elements are viewed as ‘selfish genetic elements’, yet they contribute to gene regulation and genome evolution in diverse ways 1 . More than half of the human genome consists of transposable elements 2 . Alu elements belong to the short interspersed nuclear element (SINE) family of repetitive elements, and with over 1 million insertions they make up more than 10% of the human genome 2 . Despite their abundance and the potential evolutionary advantages they confer, Alu elements can be mutagenic to the host as they can act as splice acceptors, inhibit translation of mRNAs and cause genomic instability 3 . Alu elements are the main targets of the RNA-editing enzyme ADAR 4 and the formation of Alu exons is suppressed by the nuclear ribonucleoprotein HNRNPC 5 , but the broad effect of massive secondary structures formed by inverted-repeat Alu elements on RNA processing in the nucleus remains unknown. Here we show that DHX9, an abundant 6 nuclear RNA helicase 7 , binds specifically to inverted-repeat Alu elements that are transcribed as parts of genes. Loss of DHX9 leads to an increase in the number of circular-RNA-producing genes and amount of circular RNAs, translational repression of reporters containing inverted-repeat Alu elements, and transcriptional rewiring (the creation of mostly nonsensical novel connections between exons) of susceptible loci. Biochemical purifications of DHX9 identify the interferon-inducible isoform of ADAR (p150), but not the constitutively expressed ADAR isoform (p110), as an RNA-independent interaction partner. Co-depletion of ADAR and DHX9 augments the double-stranded RNA accumulation defects, leading to increased circular RNA production, revealing a functional link between these two enzymes. Our work uncovers an evolutionarily conserved function of DHX9. We propose that it acts as a nuclear RNA resolvase that neutralizes the immediate threat posed by transposon insertions and allows these elements to evolve as tools for the post-transcriptional regulation of gene expression.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/114/2163 / 631/208/176 / 631/45/500 / 631/80/641/2002 / Adenosine Deaminase - chemistry / Adenosine Deaminase - deficiency / Adenosine Deaminase - genetics / Adenosine Deaminase - isolation & purification / Adenosine Deaminase - metabolism / Alu Elements - genetics / Amino acids / Animals / Cell Line / DEAD-box RNA Helicases - deficiency / DEAD-box RNA Helicases - genetics / DEAD-box RNA Helicases - metabolism / Evolution, Molecular / Exons - genetics / Gene Expression Regulation / Genes, Reporter - genetics / Genetic research / Genome, Human - genetics / Genomes / Genomics / HEK293 Cells / Human genome / Humanities and Social Sciences / Humans / Inverted Repeat Sequences - genetics / letter / Male / Methods / Mice / multidisciplinary / Mutagenesis - genetics / Neoplasm Proteins - deficiency / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Nucleic Acid Conformation / Protein Binding / Protein Biosynthesis / Protein Isoforms - chemistry / Protein Isoforms - genetics / Protein Isoforms - isolation & purification / Protein Isoforms - metabolism / Proteins / RNA / RNA - biosynthesis / RNA - chemistry / RNA - genetics / RNA - metabolism / RNA Editing - genetics / RNA, Double-Stranded - chemistry / RNA, Double-Stranded - genetics / RNA, Double-Stranded - metabolism / RNA-Binding Proteins - chemistry / RNA-Binding Proteins - genetics / RNA-Binding Proteins - isolation & purification / RNA-Binding Proteins - metabolism / Science / Stem cells / Transcription, Genetic