{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ATXN7L3 is a key non‐enzymatic adaptor subunit of the SAGA (Spt–Ada–GCN5 acetyltransferase) complex that, together with USP22 and ENY2, forms the deubiquitination module responsible for removing monoubiquitin from histone H2B. This activity is critical to counteracting heterochromatin silencing and enabling full transcriptional activation by nuclear receptors and other activators."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Inactivation or downregulation of ATXN7L3 leads to elevated global levels of H2B ubiquitination, thereby perturbing the finely tuned chromatin dynamics required for proper gene expression. In addition, regulation of ATXN7L3 is implicated in human cancers. For example, in cervical cancer, an oncogenic long noncoding RNA modulates a microRNA (miR‑877‑5p)/ATXN7L3 axis, which in turn influences cell proliferation, migration, and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural analyses have demonstrated that ATXN7L3 contains a conserved SCA7 zinc‐finger domain, which is essential for its integration and function within the deubiquitination module."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Aberrant forms of ATXN7L3, such as those generated by fusion with UBTF in a subset of high‐risk B–progenitor acute lymphoblastic leukemia cases, further underscore its potential involvement in oncogenic transformation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, post‐transcriptional regulation by microRNAs (e.g. let‑7) has been shown to target ATXN7L3 mRNA, thereby contributing to alterations in H2Bub1 levels and impacting transcriptional programs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, studies comparing ATXN7L3 with its paralog ATXN7L3B have revealed that these two proteins can compete for association with ENY2. While overexpression of ATXN7L3 promotes deubiquitinase activity and reduces H2Bub1 levels, ATXN7L3B overexpression has the opposite effect—elevating H2Bub1—and influences cellular processes such as migration and estrogen receptor signaling in breast cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Consistent with these roles, in hepatocellular carcinoma ATXN7L3 acts as a coactivator for ERα‐mediated transactivation, enhancing the transcription of tumor‐suppressive genes such as SMAD7; lower expression of ATXN7L3 correlates with increased tumor growth and poorer clinical outcomes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings position ATXN7L3 as a multifaceted regulator of chromatin structure and gene transcription. Its proper function is essential for maintaining balanced histone ubiquitination and correct transcriptional responses, while its dysregulation or aberrant fusion can contribute to diverse human pathologies—including several cancers—thereby making it a promising target for therapeutic intervention.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yue Zhao, Guillaume Lang, Saya Ito, et al. 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