{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUbiquitin‐specific protease 5 (USP5), also known as isopeptidase T, is a deubiquitinating enzyme that disassembles free, unanchored polyubiquitin chains into monoubiquitin. Detailed structural investigations—including crystallographic studies and mutagenesis—have revealed that USP5 contains multiple zinc‐finger ubiquitin binding (ZnF UBP) domains that are crucial for recognizing the C‐terminal diglycine motif of ubiquitin and for allosterically activating its catalytic core. These studies have defined key catalytic residues and demonstrated that distinct ZnF domains contribute separately to substrate targeting and to the core hydrolytic function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBy catalyzing the removal of unanchored polyubiquitin chains, USP5 is a key regulator of cellular ubiquitin homeostasis. Its activity facilitates the clearance of polyubiquitin signals at sites of DNA damage—thereby promoting efficient homologous recombination repair—and modulates the assembly and disassembly of stress granules during heat shock. Moreover, interactions with proteins such as DC‐UbP (a ubiquitin‐like shuttle factor) help coordinate overall cellular ubiquitination and deubiquitination dynamics."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDysregulation of USP5 has emerged as an important factor in tumorigenesis. In several cancers, USP5 exerts oncogenic effects by deubiquitinating and thereby stabilizing key regulatory proteins. For instance, knockdown of USP5 leads to p53 stabilization by impeding proteasomal recognition of ubiquitinated p53"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "; conversely, USP5 deubiquitinates oncoproteins such as SLUG in hepatocellular carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", c‐Maf in multiple myeloma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", PD‐L1 in non‐small cell lung cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", HIF2α in breast cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", and FoxM1 in pancreatic ductal adenocarcinoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " USP5 also features in regulatory cascades initiated by noncoding RNAs—for example, the circHECTD1/miR-1256/USP5 axis in gastric cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "—and in the control of β-catenin signaling via DEPDC1B in breast cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " In bladder cancer, USP5-mediated deubiquitination of Twist1 contributes to enhanced invasion"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", while its upregulation in cholangiocarcinoma further implicates it in tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Pan-cancer analyses also show that USP5 is frequently overexpressed and that elevated levels correlate with poor clinical outcomes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ", whereas regulation by E3 ligases such as Smurf1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "and quality-control partners like SGTA"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "underscore its multifaceted role in oncogenic signaling.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in cancer and proteostasis, USP5 is implicated in inflammatory and stress‐related processes. 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