USP5,also named as ISOT,belongs to the peptidase C19 family. Knock-down of USP5 causes the accumulation of TP53/p53 and an increase in TP53/p53 transcriptional activity because the unanchored polyubiquitin that accumulates is able to compete with ubiquitinated TP53/p53 but not with MDM2 for proteasomal recognition. USP5 is a potential target for p53 activating therapeutic agents for the treatment of cancer. It is a novel proteasome associated protein. USP5 cleaves linear and branched multiubiquitin polymers with a marked preference for branched polymers.