Radiation therapy which causes a variety of DNA lesions including DSBs damage continues to be a mainstay in the treatment of an assortment of malignancies . However, tumor cells as seen in many cancers often display resistance to standardized radiation therapy due to hyperactive DSB repair mechanisms . Therefore, developing drugs aimed at modulating DSB repair activity has provided a profound avenue for many commonly used chemotherapy and radiotherapy regimens. One of the well-known cases is the utilization of platinum salts which is frequently given in patients with advanced ovarian cancer . Platinum salts (carboplatin or cisplatin) can cause DNA inter- and intrastrand crosslinks damages that are recognized and repaired by a combination of nucleotide excision repair (NER) and HR . It has been estimated that nearly half of high-grade serous ovarian cancers have germ line or somatic mutations in BRCA1 or BRCA2 [38, 39]. Many DSB repair proteins are now being used as biomarkers to direct the use of therapy (Table 2). Although tumor cells defective in the repair genes show sensitivity toward genotoxic agents in the first place, after an unpredictable period, hyperactivity of the repair proteins due to re-emergence, reversal or overlapping compensatory pathways can make cancer cells resistant and account for the relapse . This is especially true also in ovarian cancer, in which more than 42% of the carboplatin-resistant tumors tested had secondary mutations that restored the BRCA1 or BRCA2 open reading frames . Tumor cells are highly heterogenous and have the ability to develop either intrinsic or acquired resistance phenotype through molecular alterations. This poses a major challenge to cancer treatment. One possible way to overcome or delay the development of chemoresistance is to ‘re-sensitize’ tumors to the original treatment with the help of new identified targets.