{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRIOX1, also known as NO66, is a JmjC domain‐containing enzyme that functions as a histone demethylase with specificity toward H3K4me and H3K36me marks. It interacts directly with key osteogenic transcription factors—most notably Osterix (Osx)—thereby modulating osteoblast‐specific gene expression and affecting bone formation. Structural studies have revealed that NO66 assembles into higher order oligomers (typically tetramers) and that this oligomerization is critical for its ability to inhibit Osx-dependent promoter activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiochemical and structural analyses further demonstrate that NO66/RIOX1 exhibits additional enzymatic activities. It catalyzes hydroxylation reactions—as seen in its modification of ribosomal protein Rpl8—and recognizes substrates via a conserved NHXH motif. NO66 is predominantly a nucleolar protein; however, it also localizes to distinct nucleoplasmic domains associated with heterochromatic clusters. These findings suggest that beyond its role in osteoblast differentiation, NO66 participates in ribosome biogenesis and chromatin remodeling by modulating epigenetic marks."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, aberrant expression of NO66/RIOX1 has been correlated with several pathological conditions. Elevated NO66 levels are observed in certain cancers—including prostate cancer, glioblastoma, and acute myeloid leukemia—where it appears to promote tumor cell survival, proliferation, and invasiveness through its epigenetic regulatory functions. In addition, in non-neoplastic contexts such as chronic kidney disease and cardiomyocyte injury, altered NO66 expression is linked to changes in cell survival pathways (for example, via modulation of PI3K/Akt signaling), underscoring its potential impact on tissue homeostasis and apoptosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jens Eilbracht, Michaela Reichenzeller, Michaela Hergt, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Purification, crystallization and preliminary crystallographic analysis of histone lysine demethylase NO66 from Homo sapiens."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Crystallogr Sect F Struct Biol Cryst Commun (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1107/S174430911201740X"}], "href": "https://doi.org/10.1107/S174430911201740X"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22750859"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22750859"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yue Tao, Minhao Wu, Xing Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural insights into histone demethylase NO66 in interaction with osteoblast-specific transcription factor osterix and gene repression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.446849"}], "href": "https://doi.org/10.1074/jbc.M112.446849"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23620590"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23620590"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Chengliang Wang, Qiongdi Zhang, Tianrong Hang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure of the JmjC domain-containing protein NO66 complexed with ribosomal protein Rpl8."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Crystallogr D Biol Crystallogr (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1107/S1399004715012948"}], "href": "https://doi.org/10.1107/S1399004715012948"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26327385"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26327385"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ana Sílvia Pires-Luís, Márcia Vieira-Coimbra, Filipa Quintela Vieira, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of histone methyltransferases as novel biomarkers for renal cell tumor diagnosis and prognostication."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Epigenetics (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15592294.2015.1103578"}], "href": "https://doi.org/10.1080/15592294.2015.1103578"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26488939"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26488939"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yujiro Nishizawa, Naohiro Nishida, Masamitsu Konno, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical Significance of Histone Demethylase NO66 in Invasive Colorectal Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Surg Oncol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1245/s10434-016-5395-9"}], "href": "https://doi.org/10.1245/s10434-016-5395-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27473587"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27473587"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Krishna M Sinha, Rozita Bagheri-Yarmand, Sharmistha Lahiri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Oncogenic and osteolytic functions of histone demethylase NO66 in castration-resistant prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41388-019-0774-x"}], "href": "https://doi.org/10.1038/s41388-019-0774-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30858546"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30858546"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Qing Wang, Pei Y Liu, Tao Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Histone Demethylase NO66 Induces Glioma Cell Proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Anticancer Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.21873/anticanres.13806"}], "href": "https://doi.org/10.21873/anticanres.13806"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31704826"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31704826"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Liping Zhang, Qin Chen, Zihong Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mechanisms Regulating Muscle Protein Synthesis in CKD."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Am Soc Nephrol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1681/ASN.2019121277"}], "href": "https://doi.org/10.1681/ASN.2019121277"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32764136"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32764136"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Hanyu Deng, Bo Yu, Yang Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NO66 overexpression rescues ethanol-induced cell apoptosis in human AC16 cardiomyocytes by suppressing PTEN and activating the PI3K/Akt signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Biochim Biophys Sin (Shanghai) (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/abbs/gmaa100"}], "href": "https://doi.org/10.1093/abbs/gmaa100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33085743"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33085743"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Weijia Yu, Christoph Lutz, Alwin Krämer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The JmjC-domain protein NO66/RIOX-1 affects the balance between proliferation and maturation in acute myeloid leukemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2021.112566"}], "href": "https://doi.org/10.1016/j.yexcr.2021.112566"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33745927"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33745927"}]}]}]}