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.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Salvati E,Rizzo A,Iachettini S,Zizza P,Cingolani C,D'Angelo C,Porru M,Mondello C,Aiello A,Farsetti A,Gilson E,Leonetti C,Biroccio Adoi
10.1093/nar/gkv006subject
Has Abstractpub_date
2015-02-18 00:00:00pages
1759-69issue
3eissn
0305-1048issn
1362-4962pii
gkv006journal_volume
43pub_type
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