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USP5 (ubiquitin carboxyl-terminal hydrolase 5) cleaves linear and branched multiubiquitin polymers with a marked preference for branched polymers. It is involved in unanchored Lys-48-linked polyubiquitin disassembly, and also binds linear and Lys-63 linked polyubiquitin with a lower affinity. Knock-down of USP5 causes the accumulation of p53/TP53 and an increase in p53/TP53 transcriptional activity because the unanchored polyubiquitin that accumulates is able to compete with ubiquitinated p53/TP53 but not with MDM2 for proteasomal recognition.
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