ORC1 and cancer: Inactivation of cullin neddylation by MLN4924 in cancer cells can accumulate multiple CRL substrates, including (1) cell cycle inhibitors such as p21, p27, and Wee1, resulting in cell cycle arrest [53]; (2) DNA replication licensing factors CDT1 and ORC1, leading to DNA re-replication stress and the DNA damage response [47,54]; and (3) IκBα, inhibiting NFκB activity [55].