Maintaining genome integrity is indispensible for cells to prevent and limit accruement of deleterious mutations and to promote viable cell growth and proliferation. Cells possess a myriad of mechanisms to detect, prevent and repair incurred cellular damage. Here we discuss various proteins and their accompanying cellular pathways that promote genome stability. We first investigate the NEDD8 protein and its role in promoting homologous recombination repair via multiple Cullin E3 ubiquitin ligases. We provide specific mechanisms through which, UBE2M, an E2 conjugating enzyme, neddylates various Cullin ligases to render them catalytically active to degrade their substrates by the proteasome. We show that CUL1, CUL2 and CUL4 are important in regulating various steps in the DNA damage response. Our data indicates that UBE2M and the neddylation pathway are important for genome stability. Our second topic discusses the role of the USP1- UAF1 deubiquitinating enzyme in promoting homologous recombination. We show that USP1-UAF1 interact with and stabilize RAD51AP1 (RAD51- Associated Protein 1). RAD51AP1 has previously been reported to promote homologous recombination by facilitating recombinase activity of RAD51, an essential protein involved in homologous recombination repair. We show that USP1, UAF1 and RAD51AP1 depletion leads to genome instability. Our data demonstrates the importance of these proteins in promoting genome integrity via homologous recombination.