Abstract A12: CTCF facilitates DNA double-strand break repair by homologous recombination

Abstract

Abstract The repair of DNA double strand breaks (DSB) is mediated via two major pathways, non-homologous end joining (NHEJ) or homologous recombination repair (HRR). Such repair is critical for cell survival and genome stability. Here, we report a new role for the multifunctional protein CTCF in facilitating the repair of DSB via the HRR pathway. CTCF is recruited to DSB through its zinc finger domain independently of poly(ADP-ribose) polymers catalyzed by PARP-1. CTCF ensures proper DSB repair kinetics in response to gamma-irradiation, and potentiates activation of the G2/M checkpoint. We find that CTCF regulates HRR through facilitating the recruitment of BRCA2, which is dependent on CTCF PARylation. In contrast, CTCF does not influence the recruitment, or retention, of the NHEJ protein 53BP1 to DSB. We also see that loss of CTCF is associated with hypersensitivity to DNA damaging inducing agents and inhibitors of PARP-1. Taken together, our findings establish for the first time that CTCF is an important regulator of the HRR pathway and indicate that tumors harboring hypo-PARylated CTCF may show elevated sensitivity to PARP inhibition. Citation Format: Khalid Hilmi, Chenxi Zhang, Zhenbao Yu, Amine Saad, Stephane Richard, Luke McCaffrey, Moulay A. Alaoui-Jamali, Michael Witcher. CTCF facilitates DNA double-strand break repair by homologous recombination [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A12.