The presynaptic phase of homologous DNA pairing and strand exchange begins with the displacement of RPA from 3'-ssDNA overhangs created by extensive resection of DNA double strand break (DSB) ends. RPA is displaced by the joint action of RAD51 and BRCA2. BRCA2 nucleates RAD51 on 3'-ssDNA overhangs, leading to formation of invasive RAD51 nucleofilaments which are stabilized by the BCDX2 complex (RAD51B:RAD51C:RAD51D:XRCC2). Stable synaptic pairing between recombining DNA molecules involves the invasion of the homologous sister chromatid duplex DNA by the RAD51 nucleofilament and base-pairing between the invading ssDNA and the complementary sister chromatid DNA strand, while the non-complementary strand of the sister chromatid DNA duplex is displaced. This results in the formation of a D-loop structure (Sung et al., 2003). PALB2 and RAD51AP1 synergistically stimulate RAD51 recombinase activity and D-loop formation. PALB2 simultaneously interacts with RAD51, BRCA2 and RAD51AP1 (Modesti et al. 2007, Wiese et al. 2007, Buisson et al. 2010, Dray et al. 2010). PALB2 also interacts with BRCA1, and this interaction fine-tunes the localization of BRCA2 and RAD51 at DNA DSBs (Zhang et al. 2009, Sy et al. 2009). The CX3 complex, composed of RAD51C and XRCC3, binds D-loop structures through interaction with PALB2 and may be involved in the resolution of Holliday junctions (Chun et al. 2013, Park et al. 2014).
While RAD52 promotes formation of invasive RAD51 nucleofilaments in yeast, human BRCA2 performs this function, while human RAD52 regulates single strand annealing (SSA) (reviewed by Ciccia and Elledge 2010).