A basal level of DNA damage and telomere deprotection increases the sensitivity of cancer cells to G-quadruplex interactive compounds

Erica Salvati, Angela Rizzo, Sara Iachettini, Pasquale Zizza, Chiara Cingolani, Carmen D'Angelo, Manuela Porru, Chiara Mondello, Aurora Aiello, Antonella Farsetti, Eric Gilson, Carlo Leonetti, Annamaria Biroccio

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1759-1769
Number of pages11
JournalNucleic Acids Research
Volume43
Issue number3
DOIs
Publication statusPublished - 2015

ASJC Scopus subject areas

  • Genetics

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