Chromosomal instability syndromes are sensitive to poly ADP-ribose polymerase inhibitors.
Poly ADP-ribose polymerase inhibitors have been shown to target cells with homologous recombination DNA repair defects. We report that poly ADP-ribose polymerase inhibitors induces apoptosis in cells deficient in other key DNA repair components. Chromosomal instability disorders, Fanconi Anemia and Bloom's syndrome have dysfunctional DNA repair and an increased likelihood of leukemic transformation. PI addition to Fanconi Anemia and Bloom's syndrome cells resulted in significant apoptosis. Furthermore, poly ADP-ribose polymerase inhibitors induced apoptosis in DNA repair signaling defective ATM(-/-) and NBS(-/-) fibroblasts. Immunocytochemistry showed homologous recombination was abrogated in NBS(-/-) and ATM(-/-) fibroblasts, compromised in Fanconi anemia and normal in Bloom's syndrome cells in response to poly ADP-ribose polymerase inhibitors. Strikingly, poly ADP-ribose polymerase inhibitors increases non-homologous end joining repair activity, whilst non-homologous end joining deficient cells are extremely sensitive to poly ADP-ribose polymerase inhibitors. These data suggest poly ADP-ribose polymerase inhibitors target cells with DNA repair and signaling defects rather than solely defects in homologous recombination improving the potential of poly ADP-ribose polymerase inhibitors therapy in a wider range of cancers.
Department of Haematological Medicine, Leukaemia Sciences Laboratories, The Rayne Institute, Kings College London, Denmark Hill Campus, London, UK.
Terry J
TJ
Gaymes
Sydney
S
Shall
Farzin
F
Farzaneh
Ghulam J
GJ
Mufti
D017209:Apoptosis / Q000187:drug effects; D001816:Bloom Syndrome / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000187:drug effects; D004260:DNA Repair; D049914:DNA Repair-Deficiency Disorders / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005199:Fanconi Anemia / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013577:Syndrome
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors