Abstract 3066: DNA ligase IV inhibitor and X-ray exert a synthetic lethal in loss-of-function p53 cells

Abstract

Abstract The majority of lung cancer patients receive radiotherapy during the treatment process. Dysfunction of DNA ligase IV impaired non-homologous end joining (NHEJ) and sensitized cells to X-ray. p53 regulated DNA damage repair and was mutated in various lung cancer cells. This study aimed to investigate the synergic effects of DNA ligase IV inhibitor SCR-7 and radiation on both wild-type and p53-deficient lung cancer cells. In the p53 wild-type cell, X-ray and SCR-7 triggered G2/M checkpoint, induced BRCA1, RAD18 activation, and promoted PCNA ubiquitination, facilitating homologous recombination (HR) and translesion synthesis (TLS) rather than NHEJ. In p53-deficient cells, SCR-7 and X-ray exerted a synthetic lethal via inducing more DNA damage, muting TLS, and impairing G2/M checkpoint as dysfunction of Cdc2 and Cyclin B1. Moreover, many cells were collapsed in mitosis catastrophe as a large number of disintegrating chromosomes, and apoptosis was significantly increased. Furthermore, the synergic effects of SCR-7 and X-ray were diminished by exogenous p53 overexpression. Therefore, we hypothesized p53 should be a major regulator of HR and TLS activation when HNEJ deficiency. Our studies indicated that patients with a loss function of p53 might benefit from SCR-7 and radiotherapy with fewer side effects. Citation Format: Tingting Lin, Zhilian Zhou, Lifeng Zhu, Yandan Fan, Xiaofen Ding, Yingming Sun. DNA ligase IV inhibitor and X-ray exert a synthetic lethal in loss-of-function p53 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3066.