title: DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome.
abstract: Transposable elements are viewed as 'selfish genetic elements', yet they contribute to gene regulation and genome evolution in diverse ways. More than half of the human genome consists of transposable elements. 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. 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. Alu elements are the main targets of the RNA-editing enzyme ADAR and the formation of Alu exons is suppressed by the nuclear ribonucleoprotein HNRNPC, 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 nuclear RNA helicase, 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.
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Tuğçe
authors.initials: T
authors.lastname: Aktaş
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: İbrahim
authors.initials: İ
authors.lastname: Avşar Ilık
authors.affiliation: Institute for Informatics, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Maticzka
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.|Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Vivek
authors.initials: V
authors.lastname: Bhardwaj
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.|Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Pessoa Rodrigues
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Mittler
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Manke
authors.affiliation: Institute for Informatics, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Backofen
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Asifa
authors.initials: A
authors.lastname: Akhtar
mesh_terms: D000243:Adenosine Deaminase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D020087:Alu Elements / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D055029:Inverted Repeat Sequences / Q000235:genetics*; D008297:Male; D051379:Mice; D016296:Mutagenesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017393:RNA Editing / Q000235:genetics*; D000079962:RNA, Circular; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D009363:Neoplasm Proteins; D020033:Protein Isoforms; D000079962:RNA, Circular; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D012313:RNA; C000595356:ADAR protein, human; D000243:Adenosine Deaminase; C098487:DHX9 protein, human; D053487:DEAD-box RNA Helicases