DNA double-strand break repair pathways have a multifaceted function in tumorigenesis and in the response to therapeutic modalities. Firstly, erroneous or deregulated DNA repair results in chromosomal abnormalities, genomic instability, and higher mutation rates, which can predispose the cells to cancer and make them vulnerable to certain kinds of genotoxic stresses . On the other hand, hyperactive DNA repair proteins due to upregulation or polymorphisms may provide survival advantages to cancer cells in therapeutic response . Defects in core HR and NHEJ proteins have been implicated in a vast repertoire of cancers (Table 1). It has been estimated that approximately half of high-grade serous ovarian adenocarcinoma samples are defective in HR repair pathway, and these HR defects are largely driven by mutations or epigenetic silencing of BRCA1 and BRCA2 genes . In terms of the major cellular sources of DSBs, evidence has shown that the DDR can be invoked and dysfunctional at an early stage in the development of neoplasia [28, 29]. The activation of oncogenes, for example, MYC and RAS can stimulate the firing of various unwanted replication forks as a major aspect of a proliferative program. These forks rapidly stall and collapse, resulting in formation of DSBs [30, 31]. Cell-cycle checkpoints are elicited to repair DNA lesions before mitosis takes place. For precancerous damage to advance to tumors, it is suggested that DSB repair factors and cell-cycle checkpoint proteins progress toward becoming inactivated. Thus, cells continue through the cell cycle with unsuccessfully repaired collapsed forks in place, resulting in tumor growth and expansion . Additionally, there is strong association between DSB repair gene mutations and an elevated risk of inherited rare diseases. Mutations in ATM, Mre11 and NBS1 are found in patients with Ataxia Telangiectasia (A-T), Ataxia Telangiectasia-like disorder (A-TLD) and Nijmegen breakage syndrome (NBS), respectively .