**1. Introduction**

The faithful repair of deoxyribonucleic acid (DNA) lesions is central to the maintenance of genomic integrity [1]. DNA double-strand breaks (DSBs) occur during normal developmental processes including meiosis, mating-type switching, V(D)J recombination, antigen receptor gene rearrangement, and also through normal activity of topoisomerase II (Top2) [2–5]. DSBs also result from exposure to exogenous sources such as ionizing radiation (IR), reactive oxygen species, and chemotherapeutic agents including inhibitors of Top2 [6–9]. Aberrant repair of DSBs may be mutagenic and result in cell lethality or promote oncogenic transformation. Repair of DSBs in eukaryotes occurs by either homology-dependent or homologyindependent (also known as end-joining or illegitimate) mechanisms [10–13]. In yeast, homology-dependent repair predominates over end-joining [10, 14]. In mammalian cells, direct examination of repair products has demonstrated the

predominant use of end-joining [13]. The majority of studies generate targeted DSBs by endonucleases or lasers, and introduce artificial repair substrates into the system [15]. However, exposure to natural compounds can lead to multiple DSBs in a variety of chromatin regions and contexts [16–20]. Understanding how cells respond to these compounds and repair damage caused by them has important implications for genome stability.

Bioflavonoids are natural compounds in soy, fruits, vegetables, tea, coffee, and wine, and contained in energy drinks and dietary supplements [21–24]. Bioflavonoids are also in pesticides and flame retardants [25–27]. Bioflavonoids inhibit the enzyme topoisomerase II (Top2) to promote DSBs, and recent studies have elucidated the cellular mechanisms used to repair the DSBs induced by bioflavonoids [16, 28, 29]. This chapter will discuss cell type differences in expression and activity of proteins in major DNA repair pathways, summarize findings of cellular response to bioflavonoids and Top2 inhibition, discuss how these compounds trigger alternative end-joining, and conclude with implications for genome instability and human disease.
