title: A basal level of DNA damage and telomere deprotection increases the sensitivity of cancer cells to G-quadruplex interactive compounds.
abstract: Here, with the aim of obtaining insight into the intriguing selectivity of G-quadruplex (G4) ligands toward cancer compared to normal cells, a genetically controlled system of progressive transformation in human BJ fibroblasts was analyzed. Among the different comparative evaluations, we found a progressive increase of DNA damage response (DDR) markers throughout the genome from normal toward immortalized and transformed cells. More interestingly, sensitivity to G4 ligands strongly correlated with the presence of a basal level of DNA damage, including at the telomeres, where the chromosome ends were exposed to the DDR without concurrent induction of DNA repair activity, as revealed by the lack of 53BP1 recruitment and telomere aberrations. The link between telomere uncapping and the response to G4 stabilization was directly assessed by showing that a partial TRF2 depletion, causing a basal level of telomere localized DDR, rendered telomerized fibroblasts prone to G4-induced telomere damage and anti-proliferative defects. Taken together these data strongly indicate that the presence of a basal level of telomere-associated DDR is a determinant of susceptibility to G4 stabilization.
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Salvati
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Rizzo
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Iachettini
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Zizza
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cingolani
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: D'Angelo
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Porru
authors.affiliation: Istituto di Genetica Molecolare, National Research Council (CNR), Pavia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Mondello
authors.affiliation: Institute of Cell Biology and Neurobiology (IBCN), CNR Rome, Italy Department of Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Aurora
authors.initials: A
authors.lastname: Aiello
authors.affiliation: Institute of Cell Biology and Neurobiology (IBCN), CNR Rome, Italy Department of Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Farsetti
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), CNRS UMR7284/INSERM U1081, University of Nice, Nice, France Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, Nice, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy biroccio@ifo.it.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
mesh_terms: D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009369:Neoplasms / Q000235:genetics*; D016615:Telomere; D014407:Tumor Cells, Cultured