Poly(ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells

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 induc...

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Bibliographic Details
Published in:Nucleic acids research 2011-05, Vol.39 (9), p.3607-3620
Main Authors: Zhang, Yong-Wei, Regairaz, Marie, Seiler, Jennifer A, Agama, Keli K, Doroshow, James H, Pommier, Yves
Format: Article
Language:English
Subjects:
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Benzimidazoles - administration & dosage
Benzimidazoles - pharmacology
Camptothecin - administration & dosage
Camptothecin - toxicity
Cell Line, Tumor
DNA Damage
DNA Repair
DNA Replication
DNA Topoisomerases, Type I - metabolism
DNA-Binding Proteins - physiology
Endonucleases - physiology
Enzyme Inhibitors - pharmacology
Genome Integrity, Repair and
Histones - analysis
Humans
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases - physiology
Topoisomerase I Inhibitors - administration & dosage
Topoisomerase I Inhibitors - toxicity
Transcription, Genetic
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkq1304