In addition, using the p53-null Saos-2 osteosarcoma cell line and p53-deficient Li–Fraumeni cell lines, Galanos et al. showed that high p21 levels influence the function of the CRL4–CDT2 ubiquitin ligase and increase levels of the licensing factors CDC6 and CDT1, which lead to defective origin licensing and replication stress, fueling genomic instability in cancer cells. Here, CDKN1A is linked to cancer.