ArticleCell death and differentiation2023
C9orf72 functions in the nucleus to regulate DNA damage repair.
Article in Cell death and differentiation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it, 32 citations in OpenAlex.
- C9orf72-related amyotrophic lateral sclerosis-frontotemporal dementia and links to the DNA damage response: a systematic review.Frontiers in molecular neuroscience · 2025Pooled it
- ASO therapy rescues NOTCH2NLC GGC repeat expansion-induced genomic damage, 3D chromatin structural abnormalities, and senescence.Nature communications · 2026Article
- Aberrant CDK4/6-driven cell-cycle reentry drives neuronal loss and defines a therapeutic target in C9orf72 ALS/FTD.iScience · 2026Article
- The role of HECT-type E3 ubiquitin ligases in DNA damage response and repair.Cell death discovery · 2025Review
- Folic acid prevents inner hair cell degeneration via genomic stability.Cell death discovery · 2025Article
- Review
- Article
- Neuroaxonal Degeneration as a Converging Mechanism in Motor Neuron Diseases (MNDs): Molecular Insights into RNA Dysregulation and Emerging Therapeutic Targets.International journal of molecular sciences · 2025Review
- Heat-shock chaperone HSPB1 mitigates poly-glycine-induced neurodegeneration via restoration of autophagic flux.Autophagy · 2025Article
- RuvBL1/2 reduce toxic dipeptide repeat protein burden in multiple models of C9orf72-ALS/FTD.Life science alliance · 2025Article
- Tandem repeat expansions and copy number variations as risk factors and diagnostic tools for amyotrophic lateral sclerosis.Frontiers in neurology · 2025Review
- Proteins Associated with Neurodegenerative Diseases: Link to DNA Repair.Biomedicines · 2024Review
- Review
- Axonopathy Underlying Amyotrophic Lateral Sclerosis: Unraveling Complex Pathways and Therapeutic Insights.Neuroscience bulletin · 2024Review
- Poly ADP-ribose signaling is dysregulated in Huntington disease.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation.Nature communications · 2024Article
- Significance of Programmed Cell Death Pathways in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- PINX1 loss confers susceptibility to PARP inhibition in pan-cancer cells.Cell death & disease · 2024Article
- Tau beyond Tangles: DNA Damage Response and Cytoskeletal Protein Crosstalk on Neurodegeneration.International journal of molecular sciences · 2024Review
- The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The hexanucleotide GGGGCC repeat expansion in the intronic region of C9orf72 is the most common cause of Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeat expansion-generated toxic RNAs and dipeptide repeats (DPRs) including poly-GR, have been extensively studied in neurodegeneration. Moreover, haploinsufficiency has been implicated as a disease mechanism but how C9orf72 deficiency contributes to neurodegeneration remains unclear. Here, we show that C9orf72 deficiency exacerbates poly-GR-induced neurodegeneration by attenuating non-homologous end joining (NHEJ) repair. We demonstrate that C9orf72 localizes to the nucleus and is rapidly recruited to sites of DNA damage. C9orf72 deficiency resulted in impaired NHEJ repair through attenuated DNA-PK complex assembly and DNA damage response (DDR) signaling. In mouse models, we found that C9orf72 deficiency exacerbated poly-GR-induced neuronal loss, glial activation, and neuromuscular deficits. Furthermore, DNA damage accumulated in C9orf72-deficient neurons that expressed poly-GR, resulting in excessive activation of PARP-1. PARP-1 inhibition rescued neuronal death in cultured neurons treated with poly-GR peptides. Together, our results support a pathological mechanism where C9orf72 haploinsufficiency synergizes with poly-GR-induced DNA double-strand breaks to exacerbate the accumulation of DNA damage and PARP-1 overactivation in C9orf72 ALS/FTD patients.
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