Abstract IA-008: Etiology of chromosomal rearrangements, and other DNA double-strand break repair outcomes

Abstract

Abstract Defining the factors that influence chromosomal double-strand breaks (DSBs) outcomes important for developing radiosensitization strategies that target the DNA damage response (DDR). In a main project in the lab, we have used Cas9 to study mechanisms of end joining (EJ) repair that affect diverse outcomes, ranging from short insertion/deletion (indels) mutations, to large chromosomal rearrangements. In particular, we have sought to define the relative contributions of canonical non-homologous end joining (C-NHEJ), and alternative end joining (ALT-EJ), on such DSB repair outcomes. For instance, I will present evidence that C-NHEJ is absolutely required for EJ between distal ends of two Cas9-induced chromosomal breaks that are joined without causing insertion/deletion mutations (No Indel EJ). Namely, C-NHEJ does not appear to be intrinsically prone to causing indels, relative to the ALT-EJ pathway. Furthermore, using No Indel EJ as a hallmark of C-NHEJ, I will present our current directions for understanding the mechanism and regulation of C-NHEJ and ALT-EJ, and targeting these pathways by DDR inhibitors. I suggest that establishing how the DDR affects distinct EJ events will reveal the ideal contexts for using DDR inhibitors during cancer therapy and inform the development of biomarkers of response. Citation Format: Jeremy M. Stark. Etiology of chromosomal rearrangements, and other DNA double-strand break repair outcomes [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-008.