PARP and Top1 inhibitors most beneficial in endonuclease-deficient cancer cells

The synergistic combination of Poly(ADP-ribose) polymerases (PARP) and Topoisomerase I (Top1) inhibitors most beneficial on endonuclease-deficient cancer cells in cancer therapies ?

This is one of the elements discussed in the recent publication by Dr Benu Brata (National Institutes of Health (USA) and Indian Association for the Cultivation of Science (India) in Nucleic Acids Research. (1)

In this paper, Dr Benu Brata Das et al. showed that the coupling of PARP1 with Tyrosyl-DNA phosphodiesterase 1 (TDP1) is determinent for transient Top1 cleavage complex single-strand breaks repair. The authors also demonstrated that PARP1 and TDP1 have a critical function with X-Ray Repair Cross-Complementing protein 1 (XRCC1). Finally, they suggested that TDP1 inhibitors could potentially be more specific alternatives to PARP inhibitors for synergistic combination with Top1 inhibitors in cancer chemotherapy.

In this work, the authors used clever in vitro cellular models to design appropriate experimental analysis such as stable isogenic HeLa cell lines stably transfected with PPAR1-shRNA (a technology already described in a previous post “PARP inhibitors are less synthetically lethal in hypoxic conditions “) and TD1-/- and PARP1-/- double-knockout DT 40 cells together with dedicated target specific antibodies like the Anti-human TDP1.

Sources:

  • (1) Benu Brata Das, Shar-yin N. Huang, Junko Murai, Ishita Rehman, Jean-Christophe Amé, Souvik Sengupta, Subhendu K. Das, Papiya Majumdar, Hongliang Zhang, Denis Biard, Hemanta K. Majumder, Valérie Schreiber and Yves Pommier “PARP1–TDP1 coupling for the repair of topoisomerase I–induced DNA damage” (2014) Nucleic Acids Research, Vol. 42 (7), 4435-4449. DOI: 10.1093/nar/gku088
  • SilenciX® technology for stable isogenic HeLa cell lines stably transfected with PPAR1-shRNA
  • PARP inhibitors (small molecules)

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