Journal article
Timeless prevents senescence-associated phenotypes and enhances DNA repair to promote esophageal cancer cell growth
Experimental cell research, v 455(1), p114828
13 Nov 2025
PMID: 41241175
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest forms of squamous cell carcinoma, comprising approximately 90% of all esophageal cancer cases. We previously demonstrated that the Fanconi anemia DNA repair (FA) pathway mitigates replication stress to preserve the self-renewal capacity of esophageal cancer cells, highlighting the critical role of minimizing replication stress in esophageal cancer proliferation. In this study, to further explore the role of replication stress in esophageal cancer growth, we investigated the function of Timeless, a key subunit of the replication fork protection complex essential for preventing replication stress. Our findings reveal that Timeless is upregulated in esophageal cancer cells, and its depletion increases sensitivity to DNA-damaging agents, inducing cellular senescence in esophageal keratinocytes. Timeless depletion also elevates the DNA damage response while reducing the expression of DNA repair proteins associated with the FA pathway and homologous recombination. Furthermore, the loss of Timeless impairs colony-forming ability in soft agar and diminishes the self-renewal capacity required to form 3D organoids. These results suggest that Timeless plays a critical role in facilitating DNA repair and esophageal cancer progression and may represent a promising target for developing effective therapeutic strategies to treat esophageal cancers.
•Esophageal squamous cell carcinoma (ESCC) is among the deadliest SCCs.•Timeless, the replication fork protection protein, is upregulated in ESCC.•Timeless prevents DNA damage and associated senescence phenotypes.•Timeless augments DNA repair capacity through the Fanconi anemia DNA repair Pathway.•Timeless promotes self-renewal capacity of esophageal cancer cells.
Metrics
6 Record Views
Details
- Title
- Timeless prevents senescence-associated phenotypes and enhances DNA repair to promote esophageal cancer cell growth
- Creators
- Chiaki Noguchi - Drexel UniversityKalisse I. Horne - Program in Molecular & Cellular Biology & GeneticsTylor Brewster - Program in Molecular & Cellular Biology & GeneticsAlyssa Duffy - Program in Molecular & Cellular Biology & GeneticsJeel P. Shah - Program in Molecular & Cellular Biology & GeneticsAmber Theriault - Program in Cancer Biology, Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of MedicineOlivia El Naggar - Program in Molecular & Cellular Biology & GeneticsSoumya Vavilala - Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USAShivani Sheth - Drexel UniversityEishi Noguchi - Drexel University
- Publication Details
- Experimental cell research, v 455(1), p114828
- Publisher
- Elsevier Inc; SAN DIEGO
- Number of pages
- 10
- Grant note
- W. W. Smith Charitable Trust: C2007, C2106 Drexel University College of Medicine
We thank members of the Noguchi laboratory, Dr. Karen Berkowitz, and Dr. Christian Sell for their support, comments, and encouragement. This work was supported by the W. W. Smith Charitable Trust (#C2007 and #C2106 to EN) and Drexel University College of Medicine.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:001650174900001
- Scopus ID
- 2-s2.0-105025678059
- Other Identifier
- 991022133621604721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Cell Biology
- Oncology