Zfp106 binds to G- quadruplex RNAs and inhibits RAN translation and formation of RNA foci caused by G4C2 repeats

• 成果类型: Article
• 署名作者: Celona, Barbara; Salomonsson, Sally E.; Wu, Haifan; Dang, Bobo; Kratochvil, Huong T.; Clelland, Claire D.; DeGrado, William F.; Black, Brian L.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Wichita State University; Westlake University; Westlake University; University of North Carolina; University of North Carolina Chapel Hill
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15362
• DOI: 10.1073/pnas.2220020121
• 发表日期: 2024-07-30
• 关键词: amyotrophic-lateral-sclerosis; frontotemporal dementia; ggggcc repeat; hexanucleotide repeat; phase-transitions; small molecules; c9orf72 gene; in-vitro; expansion; proteins

摘要

Expansion of intronic GGGGCC repeats in the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Transcription of the expanded repeats results in the formation of RNA- containing nuclear foci and altered RNA metabolism. In addition, repeat- associated non-AUG (RAN) translation of the expanded GGGGCC- repeat sequence results in the production of highly toxic dipeptide- repeat (DPR) proteins. GGGGCC repeat-containing transcripts form G- quadruplexes, which are associated with formation of RNA foci and RAN translation. Zfp106, an RNA- binding protein essential for motor neuron survival in mice, suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Here, we show that Zfp106 inhibits formation of RNA foci and significantly reduces RAN translation caused by GGGGCC repeats in cultured mammalian cells, and we demonstrate that Zfp106 coexpression reduces the levels of DPRs in C9orf72 patient- derived cells. Further, we show that Zfp106 binds to RNA G- quadruplexes and causes a conformational change in the G- quadruplex structure formed by GGGGCC repeats. Together, these data demonstrate that Zfp106 suppresses the formation of RNA foci and DPRs caused by GGGGCC repeats and suggest that the G- quadruplex RNA- binding function of Zfp106 contributes to its suppression of GGGGCC repeat- mediated cytotoxicity.