{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRAD21 is an evolutionarily conserved core subunit of the cohesin complex that plays a pivotal role in mediating sister chromatid cohesion, proper chromosome segregation, and high‐fidelity DNA repair. Its function is tightly regulated by post‐translational modifications and proteolytic cleavages – for example, separase‐mediated cleavage during anaphase and caspase‐dependent processing during apoptosis yield biologically active fragments that facilitate chromatid disjunction and amplify cell death signals. Recent work has also underscored the importance of a conserved LPE motif on RAD21 that enables its efficient recognition and cleavage by separase, thereby ensuring proper mitotic progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its canonical role in chromosome cohesion, RAD21 is essential for the establishment and maintenance of higher‐order chromatin architecture. By engaging with chromatin remodelers such as SNF2h and architectural proteins like CTCF, RAD21-containing cohesin complexes promote the formation of chromatin loops and insulator elements that demarcate topologically associating domains. These interactions are critical not only for regulating gene expression in normal cells but also for modulating viral transcription programs during latent and lytic infection cycles."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRAD21 is also critically important for human development. Germline mutations or copy‐number variations affecting RAD21 are associated with a spectrum of cohesinopathies—including Cornelia de Lange syndrome, chronic intestinal pseudo‐obstruction, and ocular disorders such as sclerocornea. These developmental anomalies stem from RAD21’s dual role in maintaining genomic stability and in fine-tuning transcriptional programs during embryogenesis, which can also disrupt processes such as neural crest cell migration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, aberrant RAD21 expression and mutation have been implicated in tumorigenesis, disease progression, and therapeutic resistance across multiple malignancies including breast, prostate, colorectal, myeloid cancers, oral squamous cell carcinoma, and Ewing sarcoma. Elevated RAD21 levels can enhance cell proliferation, bolster DNA repair mechanisms, and mitigate replication stress, whereas its inhibition sensitizes cancer cells to chemotherapeutic agents and triggers cell cycle arrest and apoptosis. Moreover, gene amplification and dysregulated expression of RAD21 serve as emerging prognostic biomarkers with significant therapeutic implications."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these well‐established roles, RAD21 contributes to additional aspects of genome stability. It supports centrosome integrity and proper progression of DNA replication by influencing the recruitment of replication factors and the resolution of replication stress. RAD21 is additionally implicated in telomere maintenance in cells that employ alternative lengthening of telomeres, further underscoring its multifaceted role in safeguarding genomic architecture. Furthermore, studies have explored single nucleotide polymorphisms in RAD21 as potential biomarkers for radiation‐induced tissue injury and have contrasted the functions of RAD21 with other cohesin regulators, thereby highlighting its unique contributions to cell cycle regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Haizi Cheng, Nenggang Zhang, Debananda Pati "}, {"type": "b", "children": [{"type": "t", "text": "Cohesin subunit RAD21: From biology to disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2020.144966"}], "href": "https://doi.org/10.1016/j.gene.2020.144966"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32687945"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32687945"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Feng Chen, Merideth Kamradt, Mary Mulcahy, et al. 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