Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD.

ABSTRACT: An expanded GGGGCC hexanucleotide of more than 30 repeats (termed (G4C2)₃₀₊) within C9orf72 is the most prominent mutation in familial frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) (termed C9⁺). Through an unbiased large-scale screen of (G4C2)₄₉-expressing Drosophila we identify the CDC73/PAF1 complex (PAF1C), a transcriptional regulator of RNA polymerase II, as a suppressor of G4C2-associated toxicity when knocked-down. Depletion of PAF1C reduces RNA and GR dipeptide production from (G4C2)₃₀₊ transgenes. Notably, in Drosophila, the PAF1C components Paf1 and Leo1 appear to be selective for the transcription of long, toxic repeat expansions, but not shorter, nontoxic expansions. In yeast, PAF1C components regulate the e

SUBMITTER: Goodman LD 

PROVIDER: S-EPMC6535128 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature