{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPSME3 (also known as REGγ or PA28γ) is a nuclear proteasome activator that promotes the degradation of a variety of substrates in an ATP‐ and ubiquitin‑independent manner. Acting as a molecular scaffold, PSME3 facilitates the interaction between key regulatory proteins such as p53 and its negative regulator MDM2, thereby accelerating p53 ubiquitination and turnover and attenuating apoptosis. In addition, PSME3 is subject to post‐translational modifications—including caspase‐mediated cleavage and acetylation—that modulate its assembly, subcellular localization (for example, its redistribution affecting Cajal body integrity under UV stress), and, consequently, its proteolytic function. These biochemical properties are central not only to controlling cell cycle progression and maintaining chromosomal stability but also to ensuring proper responses to various forms of cellular stress and DNA damage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn numerous cancer types—including breast, pancreatic, colorectal, thyroid, and renal carcinomas—PSME3 is frequently overexpressed and contributes to tumorigenesis through multiple mechanisms. Its enhanced activity drives the proteasomal degradation of tumor suppressors (such as p53 and cyclin‑dependent kinase inhibitors) and supports oncogenic signaling pathways, including those mediated by Wnt/β‑catenin, TGF‑β, NF‑κB, and Hippo. The upregulation of PSME3 is correlated with increased cell proliferation, epithelial–mesenchymal transition, invasion and metastasis, as well as with poor clinical outcomes and resistance to therapy. Thus, PSME3 serves not only as a key facilitator of deregulated cell cycle progression and survival in cancer cells but also as a promising prognostic marker and potential therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in proteolysis and cancer, PSME3 is a pivotal regulator of several stress‐responsive and homeostatic pathways. It participates in the orchestration of the DNA damage response through an ATM–PSME3–proteasome axis, modulating the repair of double‑strand breaks while influencing immune signaling and antigen processing. Moreover, PSME3 affects viral propagation by modulating the stability of viral regulatory proteins in infections such as those by hepatitis C virus, human T‑cell lymphotropic virus, and coxsackievirus, and it has been implicated in angiogenesis and metabolic adaptation—including the control of glycolysis and even cardiac hypertrophy via regulation of key phosphatases and transcription factors. 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