RAD51 nuclear recruitment and inhibition towards innovative strategies against pancreatic cancer
| Autor: | Marcella Manerba, Stefania Girotto, Fabrizio Schipani, Nicola Tirelli, Arianna Gennari, Andrea Armirotti, Roberto Marotta, Walter Rocchia, Giuseppina Di Stefano, Andrea Cavalli, Francesco Rinaldi, Marinella Roberti |
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| Přispěvatelé: | Schipani, Fabrizio, Manerba, Marcella, Marotta, Roberto, Gennari, Arianna, Rinaldi, Francesco, Armirotti, Andrea, Roberti, Marinella, Di Stefano, Giuseppina, Rocchia, Walter, Tirelli, Nicola, Girotto, Stefania, Cavalli, Andrea |
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Radiosensitizer chemistry DNA damage Microscale thermophoresis Anticancer drug discovery / Chemo/radiosensitizer / DNA repair / Homologous recombination / Synthetic lethality RAD51 Biophysics Peptide Homologous recombination Negative stain Nuclear localization sequence |
| DOI: | 10.1101/2021.02.03.429564 |
| Popis: | RAD51, a key player in the homologous recombination (HR) mechanism, is a critical protein to preserve genomic stability. BRCA2, upon DNA damage, promotes RAD51 fibrils disassembly and its nuclear recruitment.Here, we use BRC4, a peptide derived from the fourth BRC repeat of BRCA2; BRC4 induces RAD51 defibrillation through a ‘domino’ effect, eroding fibrils from their termini, and yielding monomeric RAD51. The congruence among several techniques (static and dynamic light scattering, negative staining transmission electron microscopy (TEM), and microscale thermophoresis) allows an accurate estimation of the kinetic and thermodynamic parameters of this process. BRC4 lacks, however, a nuclear localization sequence; therefore, it cannot transport RAD51 into the nucleus, thus behaving as a RAD51 inhibitor. Cellular assays (BxPC-3, pancreatic cancer cells) indeed show that BRC4 efficiently inhibits HR and enhances the cytotoxic effect of cisplatin, a DNA-damaging drug.The present study sheds further light on the complexity of the HR pathway, paving the way for designing peptide and small organic molecule inhibitors of RAD51 as innovative anticancer and chemo/radiosensitizer compounds. |
| Databáze: | OpenAIRE |
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