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. 2014 Oct 23;16(10):835–844. doi: 10.1016/j.neo.2014.08.008

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© 2014 Neoplasia Press, Inc. Published by Elsevier Inc.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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Schematic overview of the mechanism of action of Dbait. In irradiated and Dbait-treated cells, DNA repair signaling is perturbed leading to global inhibition of DNA repair pathways. On the one hand, Dbait recognition by the DNA-PK complex induces DNA-PK activation () and initiates the uncoordinated phosphorylation of its nuclear targets visualized by pan-nuclear γ-H2AX (). Upon creation of a DSB in the DNA, the DNA damage signaling apparatus induced by Dbait is dispersed across all the modified chromatin and inhibits the recruitment of the factors required for DSB repair at the site of the damage. This leads to both non-homologous end joining (NHEJ) and homologous recombination (HR) inhibition. On the other hand, Dbait can also be bound by PARP (major protein involved in BER and SSBR) leading to its autoPARylation and the further recruitment of different BER and SSBR proteins on Dbait molecules. These proteins are thus hijacked far from the damage leading to BER/SSBR inhibition.

Inline graphic — Schematic overview of the mechanism of action of Dbait. In irradiated and Dbait-treated cells, DNA repair signaling is perturbed leading to global inhibition of DNA repair pathways. On the one hand, Dbait recognition by the DNA-PK complex induces DNA-PK activation () and initiates the uncoordinated phosphorylation of its nuclear targets visualized by pan-nuclear γ-H2AX (). Upon creation of a DSB in the DNA, the DNA damage signaling apparatus induced by Dbait is dispersed across all the modified chromatin and inhibits the recruitment of the factors required for DSB repair at the site of the damage. This leads to both non-homologous end joining (NHEJ) and homologous recombination (HR) inhibition. On the other hand, Dbait can also be bound by PARP (major protein involved in BER and SSBR) leading to its autoPARylation and the further recruitment of different BER and SSBR proteins on Dbait molecules. These proteins are thus hijacked far from the damage leading to BER/SSBR inhibition.