Abstract 518: Ionizing radiation-induced DNA damage response decreases during induced pluripotent and embryonic stem cell differentiation

Abstract

Abstract Embryonic as well as induced pluripotent stem cells (ESC/iPSC) have a robust DNA damage response to facilitate efficient repair of DNA strand breaks as well as interstrand cross-links (ICLs). Stem cell abundance in tumors can impact the efficacy of the therapeutic agents, and such agents also have an impact on the normal tissue toxicity. Therefore, it is important to compare DNA damage repair in progenitor stem cells and their differentiated lineages since the normal tissues surrounding the tumor predominantly contain differentiated cells. We therefore asked whether the DNA damage response is altered during differentiation of embryonic as well as induced pluripotent stem cells and found that sensing of ionizing radiations, interstrand cross-linking or hydroxyurea induced DNA damage was minimally altered by cellular differentiation. Furthermore, DNA DSB repair by non-homologous end joining was minimally impacted. However, the homologous recombination of DSB repair or ICL repair was significantly reduced in differentiated cells. In addition, differentiated cells showed a reduction in the frequency of new origins of replication and increased stalled replication forks. Interestingly, similar to ESC or iPSC lines, breast tumor stem cells also exhibited a decrease in DNA damage repair by homologous recombination in differentiated cells. The defect in DNA damage repair by homologous recombination was reversed in de-differentiated cells, supporting the argument that differentiation can influence homologous recombination repair of DSBs as well as repair of ICLs. These studies have implications in modulating the therapeutic efficacy of DNA damage inducing tumor-killing agents. Citation Format: Kalpana Mujoo, Raj K. Pandita, Anjana Tiwari, Vijay Charaka, Walter N. Hittelman, Murlidhar Hegde, Haibo Wang, Clayton R. Hunt, Bhuvanesh Dave, Jenny Chang, E Brian Butler, Tej K. Pandita. Ionizing radiation-induced DNA damage response decreases during induced pluripotent and embryonic stem cell differentiation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 518.