PUBLICATION
A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression
- Authors
- Deiana, M., Andrés Castán, J.M., Josse, P., Kahsay, A., Sánchez, D.P., Morice, K., Gillet, N., Ravindranath, R., Patel, A.K., Sengupta, P., Obi, I., Rodriguez-Marquez, E., Khrouz, L., Dumont, E., Abad Galán, L., Allain, M., Walker, B., Ahn, H.S., Maury, O., Blanchard, P., Le Bahers, T., Öhlund, D., von Hofsten, J., Monnereau, C., Cabanetos, C., Sabouri, N.
- ID
- ZDB-PUB-230516-57
- Date
- 2023
- Source
- Nucleic acids research 51(12): 6264-6285 (Journal)
- Registered Authors
- von Hofsten, Jonas
- Keywords
- none
- MeSH Terms
-
- Animals
- DNA/metabolism
- DNA Damage
- DNA Replication
- G-Quadruplexes*
- Genomic Instability
- Neoplasms*/drug therapy
- Neoplasms*/genetics
- Neoplasms*/metabolism
- Oxidative Stress
- Photosensitizing Agents/pharmacology
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 37191066 Full text @ Nucleic Acids Res.
Citation
Deiana, M., Andrés Castán, J.M., Josse, P., Kahsay, A., Sánchez, D.P., Morice, K., Gillet, N., Ravindranath, R., Patel, A.K., Sengupta, P., Obi, I., Rodriguez-Marquez, E., Khrouz, L., Dumont, E., Abad Galán, L., Allain, M., Walker, B., Ahn, H.S., Maury, O., Blanchard, P., Le Bahers, T., Öhlund, D., von Hofsten, J., Monnereau, C., Cabanetos, C., Sabouri, N. (2023) A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression. Nucleic acids research. 51(12):6264-6285.
Abstract
Photodynamic therapy (PDT) ideally relies on the administration, selective accumulation and photoactivation of a photosensitizer (PS) into diseased tissues. In this context, we report a new heavy-atom-free fluorescent G-quadruplex (G4) DNA-binding PS, named DBI. We reveal by fluorescence microscopy that DBI preferentially localizes in intraluminal vesicles (ILVs), precursors of exosomes, which are key components of cancer cell proliferation. Moreover, purified exosomal DNA was recognized by a G4-specific antibody, thus highlighting the presence of such G4-forming sequences in the vesicles. Despite the absence of fluorescence signal from DBI in nuclei, light-irradiated DBI-treated cells generated reactive oxygen species (ROS), triggering a 3-fold increase of nuclear G4 foci, slowing fork progression and elevated levels of both DNA base damage, 8-oxoguanine, and double-stranded DNA breaks. Consequently, DBI was found to exert significant phototoxic effects (at nanomolar scale) toward cancer cell lines and tumor organoids. Furthermore, in vivo testing reveals that photoactivation of DBI induces not only G4 formation and DNA damage but also apoptosis in zebrafish, specifically in the area where DBI had accumulated. Collectively, this approach shows significant promise for image-guided PDT.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping