ArticleScience translational medicine2021
Loss of TGFβ signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types.
Article in Science translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 57 citations in OpenAlex.
- Impaired TGF-β signaling via AHNAK family mutations elicits an esophageal cancer subtype with sensitivities to genotoxic therapy and immunotherapy.Cancer immunology, immunotherapy : CII · 2024Trial
- Targeting inflammatory microenvironments: overcoming therapy resistance and immunosuppression.Molecular cancer · 2026Review
- Phosphoproteome landscape of ARID1A and its implications in DNA damage response and breast cancer pathogenesis.Discover oncology · 2026Article
- Reduced DPP9 levels sensitize experimental breast tumors to combinatory treatment with irradiation and Olaparib.Frontiers in oncology · 2026Article
- Emerging insights into alternative end‑joining: Mechanisms, genome instability and therapeutic opportunities in cancer (Review).International journal of oncology · 2025Review
- Tumor irradiation induced immunogenic response: the impact of DNA damage induction and misrepair.Radiation oncology (London, England) · 2025Review
- HIV-1 Vpr orchestrates ciTRAN upregulation through TGF-β induction.PLoS pathogens · 2025Article
- Revisiting the TGFβ paradox: insights from HPV-driven cancer and the DNA damage response.Nature reviews. Cancer · 2025Review
- Identification of a conserved subset of cold tumors responsive to immune checkpoint blockade.Journal for immunotherapy of cancer · 2025Article
- Harnessing transcriptional regulation of alternative end-joining to predict cancer treatment.NAR cancer · 2025Article
- DNA double-strand break-capturing nuclear envelope tubules drive DNA repair.Nature structural & molecular biology · 2024Article
- ATM and 53BP1 regulate alternative end joining-mediated V(D)J recombination.Science advances · 2024Article
- ATM inhibition exploits checkpoint defects and ATM-dependent double strand break repair in TP53-mutant glioblastoma.Nature communications · 2024Article
- DNA-PKcs suppresses illegitimate chromosome rearrangements.Nucleic acids research · 2024Article
- The Causes and Consequences of DNA Damage and Chromosomal Instability Induced by Human Papillomavirus.Cancers · 2024Review
- RNA and phosphoprotein profiles of TP53- and PTEN-knockouts in MCF10A at baseline and responding to DNA damage.Scientific data · 2024Article
- Article
- The interplay between the DNA damage response and ectonucleotidases modulates tumor response to therapy.Science immunology · 2023Review
- Molecular Pathways and Mechanisms of TGFβ in Cancer Therapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Integrated analysis of racial disparities in genomic architecture identifies a trans-ancestry prognostic subtype in bladder cancer.Molecular oncology · 2023Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 4 countries.
Funding
Abstract
Among the pleotropic roles of transforming growth factor-β (TGFβ) signaling in cancer, its impact on genomic stability is least understood. Inhibition of TGFβ signaling increases use of alternative end joining (alt-EJ), an error-prone DNA repair process that typically functions as a "backup" pathway if double-strand break repair by homologous recombination or nonhomologous end joining is compromised. However, the consequences of this functional relationship on therapeutic vulnerability in human cancer remain unknown. Here, we show that TGFβ broadly controls the DNA damage response and suppresses alt-EJ genes that are associated with genomic instability. Mechanistically based TGFβ and alt-EJ gene expression signatures were anticorrelated in glioblastoma, squamous cell lung cancer, and serous ovarian cancer. Consistent with error-prone repair, more of the genome was altered in tumors classified as low TGFβ and high alt-EJ, and the corresponding patients had better outcomes. Pan-cancer analysis of solid neoplasms revealed that alt-EJ genes were coordinately expressed and anticorrelated with TGFβ competency in 16 of 17 cancer types tested. Moreover, regardless of cancer type, tumors classified as low TGFβ and high alt-EJ were characterized by an insertion-deletion mutation signature containing short microhomologies and were more sensitive to genotoxic therapy. Collectively, experimental studies revealed that loss or inhibition of TGFβ signaling compromises the DNA damage response, resulting in ineffective repair by alt-EJ. Translation of this mechanistic relationship into gene expression signatures identified a robust anticorrelation that predicts response to genotoxic therapies, thereby expanding the potential therapeutic scope of TGFβ biology.
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