Versatile enhancement of the killing potential of anti-cancer agents achieved by peptide mimetics of the PCNA interface towards specialized DNA polymerases
Abstract Cancer cells that survive chemotherapy achieve full DNA duplication despite the accumulation of damaged DNA triggered by chemotherapy. This happens because the synthesis of DNA at damaged sites is granted by tolerance events including translesion DNA synthesis (TLS), a process that promotes...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07812-9 |
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| author | Yiovana Verónica Okraine María Belén de la Vega Sofía Venerus Arbilla Ginette Moyano Agostina P. Bertolin Horacio M. Pallarés Lisa Wiesmüller Sabrina F. Mansilla Vanesa Gottifredi |
| author_facet | Yiovana Verónica Okraine María Belén de la Vega Sofía Venerus Arbilla Ginette Moyano Agostina P. Bertolin Horacio M. Pallarés Lisa Wiesmüller Sabrina F. Mansilla Vanesa Gottifredi |
| author_sort | Yiovana Verónica Okraine |
| collection | DOAJ |
| description | Abstract Cancer cells that survive chemotherapy achieve full DNA duplication despite the accumulation of damaged DNA triggered by chemotherapy. This happens because the synthesis of DNA at damaged sites is granted by tolerance events including translesion DNA synthesis (TLS), a process that promotes the use of specialized DNA polymerases (S-Pols) for DNA synthesis. Such a crucial role of S-Pols in the promotion of damaged DNA replication prompted analyses of the cell killing effects of individual S-Pols inhibitors. Because S-Pols can compensate for each other, a global inhibition of S-Pols needs to be designed and tested. Given that S-Pols are recruited to the replisome through their PCNA binding motif, we reasoned that global displacement of S-Pols will occur when delivering a peptide with a strong PCNA binding motif. The cyclin kinase inhibitor p21 contains the strongest PCNA binding motif. Therefore, we designed a peptide representing this C-terminal, PCNA interacting region (PIR) of p21. As hypothesized by us, the PIR peptide achieved global S-Pol displacement from PCNA-associated replication factories and enhanced the cancer cell killing potential of DNA damaging agents including cisplatin, hydroxyurea, olaparib and UV irradiation. Demonstrating strong versatility, the peptide also enhanced the cytotoxicity caused by agents that do not directly provoke DNA damage such as Chk1, ATR and Wee1 inhibitors. In all cases, disrupting the PCNA binding site within the PIR peptide was sufficient to dismantle its cell killing potential. Strengthening the concept, a less potent PIR, namely derived from S-Pol eta, efficiently displaced S-Pols from replication factories exacerbating cell killing by all agents tested. These results collectively indicate that simultaneous displacement of S-Pols from PCNA can be enforced by excess levels of PIR peptides. This strategy is demonstrably valid to enhance the cancer cell killing by different DNA-damaging agents. |
| format | Article |
| id | doaj-art-b4dd400ec95d462aa0b44d4c19936928 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-b4dd400ec95d462aa0b44d4c199369282025-08-20T03:06:09ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111710.1038/s41419-025-07812-9Versatile enhancement of the killing potential of anti-cancer agents achieved by peptide mimetics of the PCNA interface towards specialized DNA polymerasesYiovana Verónica Okraine0María Belén de la Vega1Sofía Venerus Arbilla2Ginette Moyano3Agostina P. Bertolin4Horacio M. Pallarés5Lisa Wiesmüller6Sabrina F. Mansilla7Vanesa Gottifredi8Fundación Instituto Leloir—Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Fundación Instituto Leloir—Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Fundación Instituto Leloir—Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Fundación Instituto Leloir—Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Fundación Instituto Leloir—Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Fundación Instituto Leloir—Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Department of Obstetrics and Gynecology, Ulm UniversityFundación Instituto Leloir—Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Fundación Instituto Leloir—Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Abstract Cancer cells that survive chemotherapy achieve full DNA duplication despite the accumulation of damaged DNA triggered by chemotherapy. This happens because the synthesis of DNA at damaged sites is granted by tolerance events including translesion DNA synthesis (TLS), a process that promotes the use of specialized DNA polymerases (S-Pols) for DNA synthesis. Such a crucial role of S-Pols in the promotion of damaged DNA replication prompted analyses of the cell killing effects of individual S-Pols inhibitors. Because S-Pols can compensate for each other, a global inhibition of S-Pols needs to be designed and tested. Given that S-Pols are recruited to the replisome through their PCNA binding motif, we reasoned that global displacement of S-Pols will occur when delivering a peptide with a strong PCNA binding motif. The cyclin kinase inhibitor p21 contains the strongest PCNA binding motif. Therefore, we designed a peptide representing this C-terminal, PCNA interacting region (PIR) of p21. As hypothesized by us, the PIR peptide achieved global S-Pol displacement from PCNA-associated replication factories and enhanced the cancer cell killing potential of DNA damaging agents including cisplatin, hydroxyurea, olaparib and UV irradiation. Demonstrating strong versatility, the peptide also enhanced the cytotoxicity caused by agents that do not directly provoke DNA damage such as Chk1, ATR and Wee1 inhibitors. In all cases, disrupting the PCNA binding site within the PIR peptide was sufficient to dismantle its cell killing potential. Strengthening the concept, a less potent PIR, namely derived from S-Pol eta, efficiently displaced S-Pols from replication factories exacerbating cell killing by all agents tested. These results collectively indicate that simultaneous displacement of S-Pols from PCNA can be enforced by excess levels of PIR peptides. This strategy is demonstrably valid to enhance the cancer cell killing by different DNA-damaging agents.https://doi.org/10.1038/s41419-025-07812-9 |
| spellingShingle | Yiovana Verónica Okraine María Belén de la Vega Sofía Venerus Arbilla Ginette Moyano Agostina P. Bertolin Horacio M. Pallarés Lisa Wiesmüller Sabrina F. Mansilla Vanesa Gottifredi Versatile enhancement of the killing potential of anti-cancer agents achieved by peptide mimetics of the PCNA interface towards specialized DNA polymerases Cell Death and Disease |
| title | Versatile enhancement of the killing potential of anti-cancer agents achieved by peptide mimetics of the PCNA interface towards specialized DNA polymerases |
| title_full | Versatile enhancement of the killing potential of anti-cancer agents achieved by peptide mimetics of the PCNA interface towards specialized DNA polymerases |
| title_fullStr | Versatile enhancement of the killing potential of anti-cancer agents achieved by peptide mimetics of the PCNA interface towards specialized DNA polymerases |
| title_full_unstemmed | Versatile enhancement of the killing potential of anti-cancer agents achieved by peptide mimetics of the PCNA interface towards specialized DNA polymerases |
| title_short | Versatile enhancement of the killing potential of anti-cancer agents achieved by peptide mimetics of the PCNA interface towards specialized DNA polymerases |
| title_sort | versatile enhancement of the killing potential of anti cancer agents achieved by peptide mimetics of the pcna interface towards specialized dna polymerases |
| url | https://doi.org/10.1038/s41419-025-07812-9 |
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