title: G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments.
abstract: Angiogenin (ANG) is a stress-activated ribonuclease that promotes the survival of motor neurons. Ribonuclease inactivating point mutations are found in a subset of patients with ALS, a fatal neurodegenerative disease with no cure. We recently showed that ANG cleaves tRNA within anticodon loops to produce 5'- and 3'-fragments known as tRNA-derived, stress-induced RNAs (tiRNAs). Selected 5'-tiRNAs (e.g., tiRNA(Ala), tiRNA(Cys)) cooperate with the translational repressor Y-box binding protein 1 (YB-1) to displace the cap-binding complex eIF4F from capped mRNA, inhibit translation initiation, and induce the assembly of stress granules (SGs). Here, we show that translationally active tiRNAs assemble unique G-quadruplex (G4) structures that are required for translation inhibition. We show that tiRNA(Ala) binds the cold shock domain of YB-1 to activate these translational reprogramming events. We discovered that 5'-tiDNA(Ala) (the DNA equivalent of 5'-tiRNA(Ala)) is a stable tiRNA analog that displaces eIF4F from capped mRNA, inhibits translation initiation, and induces the assembly of SGs. The 5'-tiDNA(Ala) also assembles a G4 structure that allows it to enter motor neurons spontaneously and trigger a neuroprotective response in a YB-1-dependent manner. Remarkably, the ability of 5'-tiRNA(Ala) to induce SG assembly is inhibited by G4 structures formed by pathological GGGGCC repeats found in C9ORF72, the most common genetic cause of ALS, suggesting that functional interactions between G4 RNAs may contribute to neurodegenerative disease.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115; Departments of Medicine, pivanov@rics.bwh.harvard.edu panderson@rics.bwh.harvard.edu.
authors.forename: Pavel
authors.initials: P
authors.lastname: Ivanov
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Boston, MA 02115; Biological Chemistry and Molecular Pharmacology, and.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: O'Day
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115; Qatar Biomedical Research Institute, Qatar Foundation, Doha, Qatar; and School of Veterinary Medicine, Cairo University, Cairo 12211, Egypt.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Emara
authors.affiliation: Biological Chemistry and Molecular Pharmacology, and.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.affiliation: Cellular and Molecular Medicine Program, Boston Children's Hospital, Boston, MA 02115; Pediatrics, Harvard Medical School, Boston, MA 02115;
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115; Departments of Medicine, pivanov@rics.bwh.harvard.edu panderson@rics.bwh.harvard.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Anderson
mesh_terms: D000926:Anticodon; D054856:G-Quadruplexes; D006801:Humans; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D012343:RNA, Transfer / Q000737:chemistry / Q000494:pharmacology*; D012259:Ribonuclease, Pancreatic / Q000494:pharmacology*
chemical_list: D000926:Anticodon; D018696:Neuroprotective Agents; D012343:RNA, Transfer; C046366:angiogenin; D012259:Ribonuclease, Pancreatic
keywords: C9ORF72; amyotrophic lateral sclerosis; angiogenin; stress; tRNA