Targeting the NPL4 Adaptor of p97/VCP Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage while Silencing the ATR Pathway
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Research on repurposing the old alcohol-aversion drug disulfiram (DSF) for cancer treatment has identified inhibition of NPL4, an adaptor of the p97/VCP segregase essential for turnover of proteins involved in multiple pathways, as an unsuspected cancer cell vulnerability. While we reported that NPL4 is targeted by the anticancer metabolite of DSF, the bis-diethyldithiocarbamate-copper complex (CuET), the exact, apparently multifaceted mechanism(s) through which the CuET-induced aggregation of NPL4 kills cancer cells remains to be fully elucidated. Given the pronounced sensitivity to CuET in tumor cell lines lacking the genome integrity caretaker proteins BRCA1 and BRCA2, here we investigated the impact of NPL4 targeting by CuET on DNA replication dynamics and DNA damage response pathways in human cancer cell models. Our results show that CuET treatment interferes with DNA replication, slows down replication fork progression and causes accumulation of single-stranded DNA (ssDNA). Such a replication stress (RS) scenario is associated with DNA damage, preferentially in the S phase, and activates the homologous recombination (HR) DNA repair pathway. At the same time, we find that cellular responses to the CuET-triggered RS are seriously impaired due to concomitant malfunction of the ATRIP-ATR-CHK1 signaling pathway that reflects an unorthodox checkpoint silencing mode through ATR (Ataxia telangiectasia and Rad3 related) kinase sequestration within the CuET-evoked NPL4 protein aggregates.
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Cu(DDC)2 interferes with DNA replication, slowing fork progression and promoting single-stranded DNA accumulation, inducing replication stress, S-phase-specific DNA damage, and activation of homologous recombination repair.
“interferes with DNA replication, slowing fork progression and promoting single-stranded DNA accumulation, inducing replication stress, S-phase-specific DNA damage, and activation of homologous recombination repair.83”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [83]
The Discussion identifies CuET as a diethyldithiocarbamate–copper complex. Results §§3.2–3.3 report slower replication forks, evidence of single-stranded DNA, replication stress, and Rad51 foci consistent with homologous-recombination repair. However, Results §3.1 finds DNA damage preferentially in S/G2-phase cells, not exclusively in S phase as “S-phase-specific” suggests. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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- Authors
- Majera, D., Skrott, Z., Chroma, K., Merchut-Maya, J. M., Mistrik, M., & Bartek, J.
- Affiliations
- Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 77 147 Olomouc, Czech Republic
- Danish Cancer Society Research Center, 2100 Copenhagen, Denmark
- Venue
- Cells
- Publisher
- MDPI AG
- Published
- 2020-02-18
- Volume
- 9
- Issue
- 2
- Pages
- 469
- ISSN
- 2073-4409 (ISSN-L)
- PMC
- PMC7072750
- OpenAlex
- W3007127818
- Cited by
- 43
- References
- 50
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 8 · 2023: 13 · 2022: 5 · 2021: 8 · 2020: 4
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Cells (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Grantová Agentura České Republiky (GACR 17-25976S)
- Ministry of School, Education, Youth and Sports of the Czech Republic (LM2015062 Czech‐BioImaging, ENOCH No. CZ.02.1.01/0.0/0.0/16_019/0000868)
- Internal grant of the Palacky University (IGA_LF_2019_026)
- the Novo Nordisk Foundation (16854)
- the Danish National Research Foundation (project CARD: no. DNRF125)
- the Danish Cancer Society (R204-A12617)
- the Swedish Research Council (VR-MH 2014-46602-117891-30)
- Swedish Cancer Society (170176)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- disulfiram, Npl4, drug repurposing, replication stress, DNA damage response, ATR signaling, homologous recombination, single-stranded DNA, protein aggregation, cancer vulnerability
- MeSH terms
- Checkpoint Kinase 1, Valosin Containing Protein, Alcohol Deterrents, Disulfiram, DNA Damage, DNA Replication, DNA-Binding Proteins, Humans, Neoplasms, Nuclear Proteins, Signal Transduction, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Ataxia Telangiectasia Mutated Proteins, Protein Aggregation, Pathological, Protein Aggregates
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