Abstract 2410: Crucial role of the non-BRCT automodification domain of PARP1 in either DNA binding and PARP inhibitor-mediated cell toxicity

Abstract

Abstract Poly(ADP-ribose)polymerase (PARP) inhibitor (PARPi)-mediated synthetic lethality is an attractive new paradigm for cancer therapy. While it has been recently proposed some of PARPi may cause DNA single strand break (SSB)-PARP1 or -PARP2 complexes, leading to cell toxicity, the mode of action of PARPi-mediated synthetic lethality is not well understood. We analyzed DNA damage response to PARPi using an isogenic set of DT40 cells. Both PARP-1 ko mutants and PARP-1 ko mutants expressing DNA bindin domain-defficient PARP1 showed markedly more resistance to olaparib than parental DT40 cells, indicating that PARP1 binding to DNA strand break through DNA binding domain is critical in olaparib-mediated cell toxicity. While non-BRCT automodomain domain deletion mutant showed a resistant phenotype, olaparib causes similar toxicity in BRCT domain deletion mutant and parental DT40 cells. Furthermore, PARP1 localized in chromatin binding fraction in BRCT1 deletion mutant, but not in non-BRCT automodomain domain deletion mutant. These results indicate that non-BRCT automodification domain plays crucial role for the formation of stable DNA SSB-PARP1 complex and olaparib-mediated synthetic lethality. Citation Format: Jun Nakamura, Xu Tian. Crucial role of the non-BRCT automodification domain of PARP1 in either DNA binding and PARP inhibitor-mediated cell toxicity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2410. doi:10.1158/1538-7445.AM2014-2410