ORC1 and Familial prostate cancer: In prostate cancer cells, neddylation inactivation by MLN4924 blocked cullin neddylation, inhibited CRLs activity, and thus triggered DNA damage, cell cycle arrest, and apoptosis by inducing the accumulation of well-known CRLs substrates, including (1) cell cycle inhibitors p21, p27, and WEE1; (2) NF-κB inhibitor IκBα; and (3) DNA replication licensing proteins CDT1 and ORC1 (Figure 5) [14, 23, 27].