ArticleProceedings of the National Academy of Sciences of the United States of America2014
WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 83 citations in OpenAlex.
- Neuron-specific WWOX gene therapy produces dose-dependent, durable rescue in a model of WWOX-related epileptic encephalopathy.Molecular therapy. Advances · 2026Article
- WWOX maintains epidermal identity and suppresses EMT to prevent aggressive cutaneous squamous cell carcinoma.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- WWOX Induction Promotes Bcl-XCells · 2026Article
- Genetic and Functional Evidence Links Germline Biallelic Inactivating Variants in WWOX to Histological Mixed-Type Thyroid Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Review
- Adult Human, but Not Rodent, Spermatogonial Stem Cells Retain States with a Foetal-like Signature.Cells · 2024Article
- Zfra Overrides WWOX in Suppressing the Progression of Neurodegeneration.International journal of molecular sciences · 2024Review
- Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection.Cell death discovery · 2024Article
- WWOX promotes osteosarcoma development via upregulation of Myc.Cell death & disease · 2024Article
- Loss of fragile WWOX gene leads to senescence escape and genome instability.Cellular and molecular life sciences : CMLS · 2023Article
- WWOX binds MERIT40 and modulates its function in homologous recombination, implications in breast cancer.Cancer gene therapy · 2023Article
- Antineoplastic Nature ofBiology · 2023Article
- Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration.International journal of molecular sciences · 2022Article
- Role of K63-linked ubiquitination in cancer.Cell death discovery · 2022Review
- Review
- The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein.Pharmacological reviews · 2022Review
- The regulatory roles of the E3 ubiquitin ligase NEDD4 family in DNA damage response.Frontiers in physiology · 2022Review
- Review
- Modeling genetic epileptic encephalopathies using brain organoids.EMBO molecular medicine · 2021Article
- Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Genomic instability is a hallmark of cancer. The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells.
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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.