G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

Pavel Ivanov, Elizabeth O'Day, Mohamed Emara, Gerhard Wagner, Judy Lieberman, Paul Anderson

Research output: Contribution to journalArticle

96 Citations (Scopus)

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., tiRNAAla, tiRNACys) 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 tiRNAAla binds the cold shock domain of YB-1 to activate these translational reprogramming events. We discovered that 5′-tiDNAAla (the DNA equivalent of 5′-tiRNAAla) is a stable tiRNA analog that displaces eIF4F from capped mRNA, inhibits translation initiation, and induces the assembly of SGs. The 5′-tiDNAAla 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′-tiRNAAla 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.

Original languageEnglish
Pages (from-to)18201-18206
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number51
DOIs
Publication statusPublished - 23 Dec 2014

Fingerprint

G-Quadruplexes
Neuroprotective Agents
Transfer RNA
RNA
Protein Biosynthesis
Motor Neurons
Ribonucleases
Neurodegenerative Diseases
Y-Box-Binding Protein 1
Anticodon
Point Mutation
Shock
angiogenin
DNA

Keywords

  • Amyotrophic lateral sclerosis
  • Angiogenin
  • C9ORF72
  • Stress
  • tRNA

ASJC Scopus subject areas

  • General

Cite this

G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments. / Ivanov, Pavel; O'Day, Elizabeth; Emara, Mohamed; Wagner, Gerhard; Lieberman, Judy; Anderson, Paul.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 51, 23.12.2014, p. 18201-18206.

Research output: Contribution to journalArticle

Ivanov, Pavel ; O'Day, Elizabeth ; Emara, Mohamed ; Wagner, Gerhard ; Lieberman, Judy ; Anderson, Paul. / G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 51. pp. 18201-18206.
@article{dd949bc66da64b27b829a4bc90ce5591,
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., tiRNAAla, tiRNACys) 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 tiRNAAla binds the cold shock domain of YB-1 to activate these translational reprogramming events. We discovered that 5′-tiDNAAla (the DNA equivalent of 5′-tiRNAAla) is a stable tiRNA analog that displaces eIF4F from capped mRNA, inhibits translation initiation, and induces the assembly of SGs. The 5′-tiDNAAla 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′-tiRNAAla 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.",
keywords = "Amyotrophic lateral sclerosis, Angiogenin, C9ORF72, Stress, tRNA",
author = "Pavel Ivanov and Elizabeth O'Day and Mohamed Emara and Gerhard Wagner and Judy Lieberman and Paul Anderson",
year = "2014",
month = "12",
day = "23",
doi = "10.1073/pnas.1407361111",
language = "English",
volume = "111",
pages = "18201--18206",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "51",

}

TY - JOUR

T1 - G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments

AU - Ivanov, Pavel

AU - O'Day, Elizabeth

AU - Emara, Mohamed

AU - Wagner, Gerhard

AU - Lieberman, Judy

AU - Anderson, Paul

PY - 2014/12/23

Y1 - 2014/12/23

N2 - 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., tiRNAAla, tiRNACys) 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 tiRNAAla binds the cold shock domain of YB-1 to activate these translational reprogramming events. We discovered that 5′-tiDNAAla (the DNA equivalent of 5′-tiRNAAla) is a stable tiRNA analog that displaces eIF4F from capped mRNA, inhibits translation initiation, and induces the assembly of SGs. The 5′-tiDNAAla 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′-tiRNAAla 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.

AB - 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., tiRNAAla, tiRNACys) 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 tiRNAAla binds the cold shock domain of YB-1 to activate these translational reprogramming events. We discovered that 5′-tiDNAAla (the DNA equivalent of 5′-tiRNAAla) is a stable tiRNA analog that displaces eIF4F from capped mRNA, inhibits translation initiation, and induces the assembly of SGs. The 5′-tiDNAAla 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′-tiRNAAla 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.

KW - Amyotrophic lateral sclerosis

KW - Angiogenin

KW - C9ORF72

KW - Stress

KW - tRNA

UR - http://www.scopus.com/inward/record.url?scp=84919934354&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84919934354&partnerID=8YFLogxK

U2 - 10.1073/pnas.1407361111

DO - 10.1073/pnas.1407361111

M3 - Article

C2 - 25404306

AN - SCOPUS:84919934354

VL - 111

SP - 18201

EP - 18206

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 51

ER -