biostudies-literatureLi SHHS | NIH | National Institute of General Medical SciencesHHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin DiseasesHHS | NIH | National Institute of Neurological Disorders and StrokeNINDS NIH HHSNIAMS NIH HHSNIGMS NIH HHS25104-25115https://www.ebi.ac.uk/biostudies/studies/S-EPMC7547246biostudies-literatureUnknown117(40)Maintaining the fidelity of nascent peptide chain (NP) synthesis is essential for proteome integrity and cellular health. Ribosome-associated quality control (RQC) serves to resolve stalled translation, during which untemplated Ala/Thr residues are added C terminally to stalled peptide, as shown during C-terminal Ala and Thr addition (CAT-tailing) in yeast. The mechanism and biological effects of CAT-tailing-like activity in metazoans remain unclear. Here we show that CAT-tailing-like modification of poly(GR), a dipeptide repeat derived from amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD)-associated <i>GGGGCC</i> (G4C2) repeat expansion in <i>C9ORF72</i>, contributes to disease. We find that poly(GR) can act as a mitochondria-targeting signal, causing some poly(GR) to Proceedings of the National Academy of Sciences of the United States of AmericaQuality-control mechanisms targeting translationally stalled and C-terminally extended poly(GR) associated with ALS/FTD.PMC7547246R01GM115898R01NS083417R01 GM115898R01NS084412R01 NS084412R01AR0748750R01 NS083417R01 AR074875Wu ZVogel HLi YLi SGlynn SDong JTantray ISnyder MChen SLu BfalseQuality-control mechanisms targeting translationally stalled and C-terminally extended poly(GR) associated with ALS/FTD.Maintaining the fidelity of nascent peptide chain (NP) synthesis is essential for proteome integrity and cellular health. Ribosome-associated quality control (RQC) serves to resolve stalled translation, during which untemplated Ala/Thr residues are added C terminally to stalled peptide, as shown during C-terminal Ala and Thr addition (CAT-tailing) in yeast. The mechanism and biological effects of CAT-tailing-like activity in metazoans remain unclear. Here we show that CAT-tailing-like modification of poly(GR), a dipeptide repeat derived from amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD)-associated <i>GGGGCC</i> (G4C2) repeat expansion in <i>C9ORF72</i>, contributes to disease. We find that poly(GR) can act as a mitochondria-targeting signal, causing some poly(GR) to 2020-01-01T00:00:00Z2020 Oct2025-04-04T11:53:50.062Z2025-04-04T11:53:50.062ZS-EPMC75472463295865010.1073/pnas.2005506117