title: Poly(ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells.
abstract: Poly(ADP-Ribose) (PAR) polymerase (PARP) inhibitors represent a promising class of novel anticancer agents. The present study explores the molecular rationale for combining veliparib (ABT-888) with camptothecin (CPT) and its clinical derivatives, topotecan and irinotecan. ABT-888 inhibited PAR induction by CPT and increased CPT-induced cell killing and histone γH2AX. Increased DNA breaks by ABT-888 were not associated with a corresponding increase of topoisomerase I cleavage complexes and were further increased by inactivation of tyrosyl-DNA phosphodiesterase 1. SiRNA knockdown for the endonuclease XPF-ERCC1 reduced the ABT-888-induced γH2AX response in non-replicating and replicating cells but enhanced the antiproliferative effect of ABT-888 in CPT-treated cells. Our findings indicate the involvement of XPF-ERCC1 in inducing γH2AX response and repairing topoisomerase I-induced DNA damage as an alternative pathway from PARP and tyrosyl-DNA phosphodiesterase 1.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: Yong-Wei
authors.initials: YW
authors.lastname: Zhang
authors.forename: Marie
authors.initials: M
authors.lastname: Regairaz
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Seiler
authors.forename: Keli K
authors.initials: KK
authors.lastname: Agama
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000633:toxicity*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004720:Endonucleases / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006657:Histones / Q000032:analysis; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D014158:Transcription, Genetic
chemical_list: D001562:Benzimidazoles; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D006657:Histones; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D059004:Topoisomerase I Inhibitors; C095888:xeroderma pigmentosum group F protein; C521013:veliparib; D011065:Poly(ADP-ribose) Polymerases; C071447:ERCC1 protein, human; D004720:Endonucleases; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin