ArticleNucleic acids research2018
Combined deficiency of Senataxin and DNA-PKcs causes DNA damage accumulation and neurodegeneration in spinal muscular atrophy.
Article in Nucleic acids research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 85 citations in OpenAlex.
- Survival motor neuron protein-independent amelioration of spinal muscular atrophy by pharmacological inhibition of c-Jun-NHBrain communications · 2026Article
- Article
- Senataxin and DNA-PKcs redundantly promote non-homologous end joining repair of DNA double strand breaks during V(D)J recombination.Science advances · 2025Article
- The Dynamic Interactions of m6A Modification and R-Loops: Implications for Genome Stability.Epigenomes · 2025Review
- Review
- How do neurons live long and healthy? The mechanism of neuronal genome integrity.Frontiers in neuroscience · 2025Review
- Oxidative genomic or genotoxic stress in neurodegeneration: Mechanisms and therapeutic avenues.AIMS neuroscience · 2025Review
- The multifaceted roles of the Ctf4 replisome hub in the maintenance of genome integrity.DNA repair · 2024Review
- Senataxin mediates R-loop resolution on HPV episomes.Journal of virology · 2024Article
- R-loops and impaired autophagy trigger cGAS-dependent inflammation via micronuclei formation in Senataxin-deficient cells.Cellular and molecular life sciences : CMLS · 2024Article
- The multifaceted functions of DNA-PKcs: implications for the therapy of human diseases.MedComm · 2024Review
- The Neglected Sibling: NLRP2 Inflammasome in the Nervous System.Aging and disease · 2024Review
- Bridging the gap: R-loop mediated genomic instability and its implications in neurological diseases.Epigenomics · 2024Review
- Role of senataxin in R-loop-mediated neurodegeneration.Brain communications · 2024Review
- Enhanced expression of the human Survival motor neuron 1 gene from a codon-optimised cDNA transgene in vitro and in vivo.Gene therapy · 2023Article
- SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration.Acta neuropathologica · 2023Article
- WNT-β Catenin Signaling as a Potential Therapeutic Target for Neurodegenerative Diseases: Current Status and Future Perspective.Diseases (Basel, Switzerland) · 2023Review
- Human senataxin is a bona fide R-loop resolving enzyme and transcription termination factor.Nucleic acids research · 2023Article
- FANCD2 promotes mitotic rescue from transcription-mediated replication stress in SETX-deficient cancer cells.Communications biology · 2022Article
- TGS1 impacts snRNA 3'-end processing, ameliorates survival motor neuron-dependent neurological phenotypes in vivo and prevents neurodegeneration.Nucleic acids research · 2022Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
Chronic low levels of survival motor neuron (SMN) protein cause spinal muscular atrophy (SMA). SMN is ubiquitously expressed, but the mechanisms underlying predominant neuron degeneration in SMA are poorly understood. We report that chronic low levels of SMN cause Senataxin (SETX)-deficiency, which results in increased RNA-DNA hybrids (R-loops) and DNA double-strand breaks (DSBs), and deficiency of DNA-activated protein kinase-catalytic subunit (DNA-PKcs), which impairs DSB repair. Consequently, DNA damage accumulates in patient cells, SMA mice neurons and patient spinal cord tissues. In dividing cells, DSBs are repaired by homologous recombination (HR) and non-homologous end joining (NHEJ) pathways, but neurons predominantly use NHEJ, which relies on DNA-PKcs activity. In SMA dividing cells, HR repairs DSBs and supports cellular proliferation. In SMA neurons, DNA-PKcs-deficiency causes defects in NHEJ-mediated repair leading to DNA damage accumulation and neurodegeneration. Restoration of SMN levels rescues SETX and DNA-PKcs deficiencies and DSB accumulation in SMA neurons and patient cells. Moreover, SETX overexpression in SMA neurons reduces R-loops and DNA damage, and rescues neurodegeneration. Our findings identify combined deficiency of SETX and DNA-PKcs stemming downstream of SMN as an underlying cause of DSBs accumulation, genomic instability and neurodegeneration in SMA and suggest SETX as a potential therapeutic target for SMA.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.