ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Paclitaxel-Induced Germline DNA-Damage Signatures Independent of Mismatch Repair in C. elegans
Provisionally accepted
- Duke Kunshan University, Kunshan, China
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Introduction: Paclitaxel is a frontline chemotherapeutic agent that stabilizes microtubules, but its broader impact on germline genome stability and long-term tolerance mechanisms remains incompletely understood. Methods: Using Caenorhabditis elegans, we combined phenotypic, cytological, genetic, and transcriptomic approaches, and further validated selected findings in human A498 renal carcinoma cells. Results: Paclitaxel markedly impaired fertility: hatching dropped approximately 54%, larval arrest increased approximately 4.1-fold, and brood size decreased approximately 31% at 50 μM (all P<0.01). HIM progeny rose 15-fold, with 52% of nuclei lacking SYP-1 and widespread abnormal chromosome clustering. RAD-51 foci persisted and late-pachytene apoptosis increased 47%, indicating defective DNA damage repair. Transcriptomic analysis revealed upregulation of detoxification and immune pathways and selective downregulation of mismatch repair genes; however, genetic manipulation confirmed that MMR attenuation is a stress signature rather than a causal driver. Multigenerational exposure led to initial sensitization (F5 survival 18.9%) followed by partial recovery (F10 survival 60.1%). Parallel experiments in human kidney cancer cells revealed concentration-dependent apoptosis, reflecting the phenotypes observed in nematodes. Conclusion: This integrated analysis establishes C. elegans as a tractable in vivo platform for dissecting both proliferative and meiotic consequences of paclitaxel. By linking spindle disruption, delayed DNA repair, and apoptosis with transcriptional reprogramming, the study provides mechanistic insight into germline vulnerability, reproductive side effects, and potential adaptive responses relevant to chemotherapy.
Keywords: chemotherapy resistance, DNA Repair, Germline toxicity, mismatch repair (MMR), Multigenerational adaptation, Paclitaxel
Received: 01 Oct 2025; Accepted: 05 Jan 2026.
Copyright: © 2026 Hong, Liu and Kim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Hyun-Min Kim
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