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Ribosome profiling reveals novel regulation of C9ORF72 GGGGCC repeat-containing RNA translation.

RNA (New York, N.Y.) | 2022

GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia. Repeat-containing RNA is translated into dipeptide repeat (DPR) proteins, some of which are neurotoxic. Using dynamic ribosome profiling, we identified three translation initiation sites in the intron upstream of (G4C2) repeats; these sites are detected irrespective of the presence or absence of the repeats. During translocation, ribosomes appear to be stalled on the repeats. An AUG in the preceding C9ORF72 exon initiates a uORF that inhibits downstream translation. Polysome isolation indicates that unspliced (G4C2) repeat-containing RNA is a substrate for DPR protein synthesis. (G4C2) repeat-containing RNA translation is 5' cap-independent but inhibited by the initiation factor DAP5, suggesting an interplay with uORF function. These results define novel translational mechanisms of expanded (G4C2) repeat-containing RNA in disease.

Pubmed ID: 34848561 RIS Download

Research resources used in this publication

None found

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Associated grants

  • Agency: NINDS NIH HHS, United States
    Id: RF1 NS101986
  • Agency: NCI NIH HHS, United States
    Id: R01 CA207893
  • Agency: NINDS NIH HHS, United States
    Id: R21 NS119952
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM135087
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM046779
  • Agency: NINDS NIH HHS, United States
    Id: R21 NS109847
  • Agency: NINDS NIH HHS, United States
    Id: R21 NS112766
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS101986
  • Agency: NCI NIH HHS, United States
    Id: R01 CA248397
  • Agency: NINDS NIH HHS, United States
    Id: R37 NS057553
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS057553

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