A D-loop can be cleaved by the complex of MUS81 and EME1 (MUS81:EME1) or MUS81 and EME2 (MUS81:EME2) and resolved without the formation of double Holliday junctions, generating cross-over products. All steps involved in this process have not been elucidated (Osman et al. 2003, Schwartz et al. 2012, Pepe and West 2014).

Alternatively, double Holliday junctions can be created by ligation of crossed-strand intermediates. Double Holliday junctions can then be resolved through the action of the BLM helicase complex known as BTRR (BLM:TOP3A:RMI1:RMI2) (Wan et al. 2013, Bocquet et al. 2014). BLM-mediated resolution of Holliday junction intermediates prevents sister chromatid exchange (SCE) between mitotic chromosomes and generates non-crossover products. SPIDR enables recruitment of the BTTR complex to the ionizing radiation-induced foci. The complex of FIGNL1 and FIRRM, which, through FIGNL1, simultaneously interacts with SPIDR (Yuan and Chen 2013) and RAD51 (Yuan and Chen 2013, Fernandes et al. 2018), may facilitate the function of SPIDR in promoting the no cross-over route of homologous recombination repair. Mitotic SCE can result in the loss-of-heterozygosity (LOH), which can make the cell homozygous for deleterious recessive mutations (e.g. in tumor suppressor genes) (Wu and Hickson 2003). Double Holliday junctions can also be resolved by cleavage, mediated by GEN1 or the SLX-MUS complex (composed of SLX1A:SLX4 heterodimer and a heterodimer of MUS81 and EME1 or, possibly, EME2). The resolvase activity of GEN1 and SLX-MUS predominantly results in crossover products, with SCE (Fekairi et al. 2009, Wyatt et al. 2013, Sarbajna et al. 2014).