{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNUCKS1 is a small (27 kDa), vertebrate‐specific, chromatin–associated protein that contains conserved nuclear localization signals (as defined in ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]) and is heavily modified by phosphorylation, acetylation, methylation, and formylation (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "]). These posttranslational modifications likely regulate its flexible DNA–binding domain—resembling that of HMGA proteins—and its ability to interact with other proteins. In functional studies, NUCKS1 has been shown to promote efficient DNA repair via homologous recombination, with its depletion impairing repair and destabilizing replication fork progression (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "]). Moreover, NUCKS1 plays a critical role in cell cycle regulation; upon mitogenic stimulation it helps drive the G1/S transition by upregulating SKP2 expression and, consequently, promoting the degradation of cyclin-dependent kinase inhibitors p21 and p27 (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "]). Its function further extends to transcriptional regulation, as it modulates chromatin accessibility and RNA polymerase II recruitment to key promoters, including that of the insulin receptor, thereby influencing energy homeostasis and glucose metabolism (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central roles in genome maintenance and cell cycle control, deregulation of NUCKS1 has been consistently linked to oncogenic processes. Multiple studies document its upregulation in diverse cancer types—including colorectal (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "]), breast (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "]), skin (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "]), gastric (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "]), ovarian (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "]), hepatocellular (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "]), and non–small cell lung cancers (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "]). In lung cancer models, for example, microRNA–137 downregulates NUCKS1 expression, thereby enhancing chemosensitivity and suppressing tumor cell proliferation and migration (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "]). Additionally, during embryonic development, dynamic changes in NUCKS1 expression correlate with periods of apoptosis and differentiation, suggesting it may help regulate tissue homeostasis (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "]). Interactions with other proteins, such as the demonstrable binding to RAD54 (a DNA motor protein) and, in osteosarcoma, stabilization via NUCB2, further underscore its multifaceted role in maintaining genomic integrity and modulating cellular responses.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic and clinical association studies further extend the functional importance of NUCKS1. Variants within the NUCKS1 locus have been linked to altered susceptibility to neurological and neuropsychiatric conditions including Parkinson’s disease (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "]), while emerging evidence also implicates it in endometriosis development (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "]). Moreover, analyses based on genome-wide association studies and proteomic profiling have repeatedly demonstrated that aberrant NUCKS1 expression may serve as a biomarker for tumor progression and recurrence in various malignancies—not only in the studies detailed above but also in additional reports exploring Parkinson’s disease (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": "]), breast cancer (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": "]), non–small cell lung cancer (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": "]), and further assessments of its diagnostic and prognostic potential have been reported in large-scale genetic studies (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": "], ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "31"}]}, {"type": "t", "text": "]). Collectively, these findings highlight NUCKS1 as not only an essential regulator of DNA repair, transcription, and cell cycle progression but also as a promising molecular marker and potential therapeutic target in a broad spectrum of human diseases.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kirsten Grundt, Ingvild V Haga, Henrik S Huitfeldt, et al. 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