Fig. 2

Double Strand Break (DSB) repair by Homologous Recombination. When a DSB is recognised, BRCA1 mediates the recruitment of the MRN complex, which comprises MRE11, RAD50 and NBS1 [3]. The MRN complex recruits ataxia-telangiectasia mutated (ATM) which, in turn, activates MRN components by phosphorylating them. The MRN complex work with CtIP and EXO1 to resect 3′ ends of the DS. Replication protein A (RPA) covers the DNA overhang to prevent it from being degraded. This stage of HR, nucleolytic processing, can be defunct in hereditary ovarian cancer; a single base mutation in exon 10 of MRE11 is reported in hereditary ovarian cancers [92] and RAD50 protein truncation is reported in hereditary breast and ovarian cancer families. As well as activating nucleolytic processing machinery, ATM phosphorylates and activates BRCA1 and RAD51. ATM is mutated in 2% of high grade EOC [7] and is significantly associated with platinum resistance [41]. Single strand DNA is unwound and the damaged chromosome invades the sister chromosome to form a Holliday junction. This occurs when RPA is replaced by RAD51, facilitated by BRCA2, allowing for strand invasion [93]. RAD51 is hypermethylated in 3% of high grade serous EOC, resulting in ineffective strand invasion [7]. MSY (not shown) is an oncogene that can silence the activation domain of BRCA2 it is overexpressed in 17% sporadic high grade serous ovarian cancer [15]