We found that depletion of Skp2 significantly increased the FBW7 and Mcl-1 interaction (Fig. 5A), enhanced IR-induced Mcl-1 ubiquitination (Fig. 4D), which was dependent on the E3 ligase FBW7 (Fig. 5E), and ultimately sensitizing CRC cells to radiotherapy both in vitro (Fig. 1) and in vivo (Fig. 6). Here, MCL1 is linked to colorectal carcinoma.