ArticleFrontiers in immunology2019
Disruption of Telomere Integrity and DNA Repair Machineries by KML001 Induces T Cell Senescence, Apoptosis, and Cellular Dysfunctions.
Article in Frontiers in immunology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 32 citations in OpenAlex.
- Naturally acquired malaria is associated with shorter leukocyte relative telomere length and increased hTERT expression in an endemic nigerian population.Frontiers in cellular and infection microbiology · 2026Article
- Immunosenescence in aging and neurodegenerative diseases: evidence, key hallmarks, and therapeutic implications.Translational neurodegeneration · 2025Review
- Immunosenescence and cancer: molecular hallmarks, tumor microenvironment remodeling, and age-specific immunotherapy challenges.Journal of hematology & oncology · 2025Review
- miR-23a-mediated TRF2 repression in CD4 T cells from PLWH.Molecular immunology · 2025Article
- Oxidative Stress in People Living With HIV: Are Diverse Supplement Sources the Solution?Health science reports · 2025Review
- Mechanisms of genotoxicity and proteotoxicity induced by the metalloids arsenic and antimony.Cellular and molecular life sciences : CMLS · 2023Review
- mActa biochimica et biophysica Sinica · 2023Review
- ROS-Induced Mitochondrial Dysfunction in CD4 T Cells from ART-Controlled People Living with HIV.Viruses · 2023Article
- Inflammation and DNA damage: cause, effect or both.Nature reviews. Rheumatology · 2023Review
- Immunosenescence of T cells: a key player in rheumatoid arthritis.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2022Review
- Immune Checkpoint Inhibitors and Other Immune Therapies in Breast Cancer: A New Paradigm for Prolonged Adjuvant Immunotherapy.Biomedicines · 2022Review
- TRF2 inhibition rather than telomerase disruption drives CD4T cell dysfunction during chronic viral infection.Journal of cell science · 2022Article
- Mitochondrial topoisomerase 1 inhibition induces topological DNA damage and T cell dysfunction in patients with chronic viral infection.Frontiers in cellular and infection microbiology · 2022Article
- The developing landscape of combinatorial therapies of immune checkpoint blockade with DNA damage repair inhibitors for the treatment of breast and ovarian cancers.Journal of hematology & oncology · 2021Review
- Complex Mechanisms of Antimony Genotoxicity in Budding Yeast Involves Replication and Topoisomerase I-Associated DNA Lesions, Telomere Dysfunction and Inhibition of DNA Repair.International journal of molecular sciences · 2021Article
- Review
- The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging.Cells · 2021Review
- Oxidative Stress Induces Mitochondrial Compromise in CD4 T Cells From Chronically HCV-Infected Individuals.Frontiers in immunology · 2021Article
- Long Non-coding RNA GAS5 Regulates T Cell Functions via miR21-Mediated Signaling in People Living With HIV.Frontiers in immunology · 2021Article
- Mitochondrial Functions Are Compromised in CD4 T Cells From ART-Controlled PLHIV.Frontiers in immunology · 2021Article
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
T cells in chronic viral infections are featured by premature aging with accelerated telomere erosion, but the mechanisms underlying telomere attrition remain unclear. Here, we employed human CD4 T cells treated with KML001 (a telomere-targeting drug) as a model to investigate the role of telomere integrity in remodeling T cell senescence. We demonstrated that KML001 could inhibit cell proliferation, cytokine production, and promote apoptosis via disrupting telomere integrity and DNA repair machineries. Specifically, KML001-treated T cells increased dysfunctional telomere-induced foci (TIF), DNA damage marker γH2AX, and topoisomerase cleavage complex (TOPcc) accumulation, leading to telomere attrition. Mechanistically, KML001 compromised telomere integrity by inhibiting telomeric repeat binding factor 2 (TRF2), telomerase, topoisomerase I and II alpha (Top1/2a), and ataxia telangiectasia mutated (ATM) kinase activities. Importantly, these KML001-induced telomeric DNA damage and T cell senescent phenotype and machineries recapitulated our findings in patients with clinical HCV or HIV infection in that their T cells were also senescent with short telomeres and thus more vulnerable to KML001-induced apoptosis. These results shed new insights on the T cell aging network that is critical and essential in protecting chromosomal telomeres from unwanted DNA damage and securing T cell survival during cell crisis upon genomic insult.
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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.