Updated project metadata. by DUBs need to be tightly controlled. Here, we identify asparagine hydroxylation as a novel posttranslational modification involved in the regulation of Cezanne (OTUD7B), a DUB that controls key cellular functions and signaling pathways. We demonstrate that Cezanne is a substrate for FIH1- and oxygen-dependent asparagine hydroxylation. FIH1 modifies Asn35 within the uncharacterized N-terminal ubiquitin-associated (UBA)-like domain of Cezanne (UBACez), which lacks conserved UBA domain properties. We show for the first time that UBACez binds Lys11-, Lys48-, Lys63- and Met1-linked ubiquitin chains in vitro, and thereby establish UBACez as a functional ubiquitin-binding domain. We reveal that interaction of UBACez with ubiquitin is mediated via a non-canonical surface, and that hydroxylation of Asn35 inhibits ubiquitin binding. Recently, it has been suggested that recruitment of Cezanne to specific target proteins depends on UBACez. Our data show that UBACez can indeed fulfil this role as regulatory domain by binding differently linked ubiquitin chains and that this interaction with ubiquitin, and thus modified substrates, can be modulated by asparagine hydroxylation.