{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nZUP1, also known as ZUFSP or C6orf113, represents a newly discovered deubiquitinating enzyme (DUB) that is distinct from the six classical DUB families. Structural and biochemical studies show that its unique catalytic domain shares a fold with UFM1‐ and Atg8-specific proteases yet employs an active site reminiscent of canonical DUB enzymes. Notably, analyses revealed that the minimal catalytic unit does not cleave polyubiquitin on its own and that proper activity requires the contribution of additional ubiquitin binding regions. In particular, two separate ubiquitin-binding domains—a helical arm (ZHA) that engages the distal ubiquitin and an atypical UBZ domain that recognizes polyubiquitin chains—are essential for conferring specificity for K63-linked polyubiquitin chains."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFunctionally, ZUP1 exerts its deubiquitinating activity by selectively targeting long K63-linked polyubiquitin chains. This selectivity, mediated by its modular arrangement of multiple ubiquitin-binding domains, enables ZUP1 to be recruited to sites of DNA damage where it plays a critical role in safeguarding genome stability. By trimming aberrant ubiquitin modifications during genotoxic stress and replication perturbations, ZUP1 helps prevent spontaneous DNA damage and promotes cellular survival under conditions of exogenous stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its enzymatic and genome-stabilizing functions, recent in-silico analyses have identified non-synonymous single nucleotide polymorphisms (nsSNPs) in ZUP1 that potentially affect its structural stability and binding affinity for ubiquitin. These pathogenic variants, which alter well-conserved residues within the protein, may compromise ZUP1’s deubiquitinating activity and thereby contribute to genetic instability and carcinogenesis. Such insights highlight the potential of these nsSNPs to serve as biomarkers for diseases associated with aberrations in ubiquitin signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Thomas Hermanns, Christian Pichlo, Ilka Woiwode, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A family of unconventional deubiquitinases with modular chain specificity determinants."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-018-03148-5"}], "href": "https://doi.org/10.1038/s41467-018-03148-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29476094"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29476094"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Dominika Kwasna, Syed Arif Abdul Rehman, Jayaprakash Natarajan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2018.02.023"}], "href": "https://doi.org/10.1016/j.molcel.2018.02.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29576527"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29576527"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Peter Haahr, Nikoline Borgermann, Xiaohu Guo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZUFSP Deubiquitylates K63-Linked Polyubiquitin Chains to Promote Genome Stability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2018.02.024"}], "href": "https://doi.org/10.1016/j.molcel.2018.02.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29576528"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29576528"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mary B Ajadi, Opeyemi S Soremekun, Adeniyi T Adewumi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional Analysis of Single Nucleotide Polymorphism in ZUFSP Protein and Implication in Pathogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Protein J (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10930-021-09962-z"}], "href": "https://doi.org/10.1007/s10930-021-09962-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33512633"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33512633"}]}]}]}