The repression of p21 expression, as implicated by the genetic inactivation of p53 and p14ARF as well as the amplification of MDM2 (p14ARF-MDM2-p53-p21) or the functional activation of USP1-IDs49, contributes to tumorigenesis by blocking osteosarcoma cells from cell-cycle exit. Here, USP1 is linked to osteosarcoma.