Abstract A134: Functional perturbation of PARP6 affects centromeric proteins and is associated with increased multi-polar spindles in breast cancer cell lines.

Poly(ADP-ribose) polymerases (PARP) are a family of 17 enzymes that catalyze the transfer of the ADP-ribose from NADH to post-translationally modify (PTM) acceptor proteins. Currently, the PTM regulation of proteins by PARPs have been demonstrated to regulate numerous signaling cascades including but not limited to DNA damage response and tumor development for PARP1-3 as well as telomere maintenance, spindle assembly, vesicular movement, and regulation of beta-catenin destruction complex for PARP5a-5b. Although progress on the biological role and therapeutic potential for some PARPs has been made, the function of and possible therapeutic application for other PARPs are not fully understood. Using cell free enzyme and cell-base multi-polar spindle assays, semi-selective PARP6 inhibitors AZ482 and AZ108 were identified. From in vitro PARP6 knock-down and AZ108 pharmacological studies in breast cancer cell lines, PARP6 perturbation was demonstrated to disrupt spindle pole clustering. To identify PARP6 protein substrate that may contribute to the spindle pole clustering defect, an in vitro acceptor protein substrate screen was performed using high-density protein microarrays containing more than 8,000 unique proteins. From this screen, an enrichment for centromeric and microtubule organizing proteins was identified. Of these centromeric PARP6 protein substrate, CHEK1 and CENP were shown to be modulated by AZ108 treatment in breast cancer cell lines. These results implicate PARP6 in a role for stablization of the spindle assembly during mitosis. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A134. Citation Format: SHAUN GROSSKURTH, Philip Petteruti, Xin Wang, Keith Mikule. Functional perturbation of PARP6 affects centromeric proteins and is associated with increased multi-polar spindles in breast cancer cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A134.