Eukaryotic cells use homologous recombination (HR), classical end-joining (C-NHEJ), and alternative end-joining (Alt-EJ) to repair DNA double-strand breaks (DSBs). Repair pathway choice is controlled by the activation and activity of pathways specific proteins in eukaryotes. Activity may be regulated by cell cycle stage, tissue type, and differentiation status. Bioflavonoids and other environmental agents such as pesticides have been shown to biochemically act as inhibitors of topoisomerase II (Top2). In cells, bioflavonoids directly lead to DNA double-strand breaks through both Top2-dependent and independent mechanisms, as well as induce DNA damage response (DDR) signaling, and promote alternative end-joining and chromosome alterations. This chapter will present differences in expression and activity of proteins in major DNA repair pathways, findings of Top2 inhibition by bioflavonoids and cellular response, discuss how these compounds trigger alternative end-joining, and conclude with implications for genome instability and human disease.
Part of the book: DNA
Maintenance of genome integrity is critical to prevent cell death or disease. Illegitimate repair of chromosomal DNA breaks can lead to mutations and genome rearrangements which are a well-known hallmark of multiple cancers and disorders. Endogenous causes of DNA double-strand breaks (DSBs) include reactive oxygen species (ROS) and replication errors while exogenous causes of DNA breaks include ionizing radiation, UV radiation, alkylating agents, and inhibitors of topoisomerase II (Top2). Recent evidence suggests that a growing list of environmental agents or toxins and natural dietary compounds also cause DNA breaks. Understanding the consequences of exposure to a broad spectrum of DSB-inducing agents has significant implications for understanding mutagenicity, genome stability and human health. This chapter will review in vivo mouse models designed to measure DNA damage and mutagenicity, and illegitimate repair of DNA DSBs caused by exposure to environmental agents.
Part of the book: Mutagenesis and Mitochondrial-Associated Pathologies