Abstract 2474: The mechanistic role of polyamines in DNA double-strand break repair

Abstract

Abstract Polyamines are essential organic cations for cell growth, proliferation and tissue remodeling. The rate-limiting step in the biosynthesis of polyamines is catalyzed by ornithine decarboxylase (ODC). The activity of ODC and the level of intracellular polyamines significantly increase in many cancers, indicating the critical role of polyamines in tumorigenesis. Depletion of polyamines sensitizes cells to DNA damage agents that lead to DNA double-strand breaks (DSBs), suggesting that endogenous polyamines may participate in DNA repair process. However, the mechanistic role of polyamines in DSB repair remains largely unknown. Here, we wish to ascertain the role of polyamines in DSBs repair pathway and to delineate the underlying mechanism by combining biochemical analyses, cell-based and animal approaches. Our cell-based experiments demonstrated that polyamines indeed participate in DNA double-strand break repair. Specifically, the level of intracellular polyamines regulates homologous recombination (HR) repair pathway rather than non-homologous end joining (NHEJ). Furthermore, our in vitro reconstitution system and functional analyses demonstrated that polyamines significantly enhance RAD51-mediated DNA strand exchange reaction. Importantly, we reveal that the stimulatory effect of polyamines by RAD51 stems from the enhancement of duplex DNA captures in the DNA exchange reaction. Finally, the physiological role of polyamines in DSBs repair was examined by using mouse hair follicle as a model system. The animal model clearly highlights the significant contribution of polyamines to the DNA repair in vivo. Our findings thus furnish valuable insight into the mechanistic basis of polyamines in DNA repair. Citation Format: Chih-Ying Lee, Guan-Chin Su, Min-Yu Ko, Wen-Yen Huang, Geen-Dong Chang, Sung-Jan Lin, Peter Chi. The mechanistic role of polyamines in DNA double-strand break repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2474. doi:10.1158/1538-7445.AM2017-2474