Cells lacking MAD2, an SAC component, can proliferate in vitro and in vivo but with increased levels of CIN.103,104 Moreover, weakening the checkpoint in mice by partially reducing the expression of various SAC genes including MAD1, MAD2, BUB1, BUBR1, and BUB3, results in premature separation of sister chromatids, chromosome missegregation, and subsequently, CIN.106–112 In addition to the SAC components, the CDK pathway also plays a significant role in CIN. This evidence concerns the gene BUB1B and cervical squamous intraepithelial neoplasia.