Abstract
It is suggested that several compounds, including G-quadruplex ligands, can target telomeres, inducing their uncapping and, ultimately, cell death. However, it has never been demonstrated whether such ligands can bind directly and quantitatively to telomeres. Here, we employed the property of platinum and platinum-G-quadruplex complexes to target G-rich sequences to investigate and quantify their covalent binding to telomeres. Using inductively coupled plasma mass spectrometry, surprisingly, we found that, in cellulo, in the presence of cisplatin, a di-functional platinum complex, telomeric DNA was platinated 13-times less than genomic DNA in cellulo, as compared to in vitro data. On the contrary, the amount of mono-functional platinum complexes (Pt-ttpy and Pt-tpy) bound either to telomeric or to genomic DNA was similar and occurred in a G-quadruplex independent-manner. Importantly, the quantification revealed that the low level of cisplatin bound to telomeric DNA could not be the direct physical cause of TRF2 displacement from telomeres. Altogether, our data suggest that platinum complexes can affect telomeres both directly and indirectly.
Highlights
Telomeres are specialized nucleoprotein structures that protect chromosome ends from being recognized as double strand breaks
We have shown that hybrid platinum complexes combining a platinum complex to a G4-ligand within the same molecule, MPQ [38], or PDC [35] induce a significant loss of TRF2 from the telomeres associated with telomere dysfunctions
The displacement of TRF2 caused by the hybrid platinum complexes was higher than the one seen with its individual components, demonstrating a synergistic effect between the coordinating PtII moiety and the G4-ligand to trigger telomere dysfunctions. These results suggest that the binding of platinum complexes to telomeric DNA can prevent TRF2 binding to telomeres, and, induce its delocalization from telomeres
Summary
Telomeres are specialized nucleoprotein structures that protect chromosome ends from being recognized as double strand breaks. Telomerase is a ribonucleoprotein, which is reactivated in 80% of cancerous cells and provide them with an unlimited proliferation due to its ability to maintain telomere length [19] Besides this role, G4 ligands can induce the displacement of TRF2 from telomeres to the nucleoplasm, without any apparent degradation of the TRF2 protein. A gradual shortening of telomeres has been observed in NER (nucleotide excision repair) deficient yeast cells [48], implying that the NER pathway involved in the reparation of cisplatin adducts [49] may play a critical role in the repair and maintenance of damaged telomeres [43] This may be related to a recent study that has shown that NER is active at telomeres since it removes the photoproducts cyclobutane pyrimidine dimers faster than the bulk genome [50].
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