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

نویسندگان

  • Yong-Wei Zhang
  • Marie Regairaz
  • Jennifer A. Seiler
  • Keli K. Agama
  • James H. Doroshow
  • Yves Pommier
چکیده

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.

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عنوان ژورنال:

دوره 39  شماره 

صفحات  -

تاریخ انتشار 2011