Similarly, p21 knockdown (Fig. 3e) significantly reduced MLN4924-induced senescence in both cell lines, as evidenced by significant reduction of SA-β-Gal positive cells (Fig. 3g and S3b).Taken together, it appears that MLN4924 mainly caused cell cycle arrest at the phase of G2, but not of M, through triggering DDR via accumulated CDT1 and ORC1, and MLN4924-induced senescence is mediated by p21, but not pRB/p16, as also demonstrated in other cancer cell types17. This evidence concerns the gene ORC1 and cancer.