This entry represents the N-terminal ubiquitin-interacting motif (UIM) found in ubiquitin carboxyl-terminal hydrolase 25 and 28, which are ubiquitin-specific proteases (USP) []. This domain provides a structural basis for the recognition and recruitment of ubiquitin substrates, potentially conferring USP display of catalytic activity [].USP25 functions in various biological processes including inflammation, immune response [, ]. It modulates the Wnt/beta-catenin pathway by deubiquitinating and stabilizing tankyrases TNKS1 and TNKS2 [, ]. USP25 regulates KEAP1-NRF2 axis in the defense against oxidative assaults by deubiquitinating KEAP1 and protecting it from degradation leading to degradation of the NRF2 transcription factor that is responsible for mounting an anti-oxidation gene expression program [].USP28 is involved in DNA damage response checkpoint and MYC proto-oncogene stability. Involved in DNA damage induced apoptosis by specifically deubiquitinating proteins of the DNA damage pathway such as CLSPN []. It is also involved in G2 DNA damage checkpoint, by deubiquitinating CLSPN, and preventing its degradation by the anaphase promoting complex/cyclosome (APC/C). In contrast, it does not deubiquitinate PLK1. It deubiquitinates ZNF304, hence preventing ZNF304 degradation by the proteasome and leading to the activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) in a subset of colorectal cancers (CRC) cells [].
