{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe Smc5/6 complex, with SMC6 as a core subunit, plays a central role in antiviral defense by restricting gene expression from extrachromosomal viral DNA. For instance, in hepatitis B virus (HBV)–infected cells the complex binds to the viral covalently closed circular DNA and represses its transcription until the virus hijacks the host’s ubiquitin ligase machinery to target Smc5/6 for degradation, thereby relieving the block on viral gene expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Similar antiviral roles are observed with other viruses: the papillomavirus E2 protein interacts with the Smc5/6 complex to support viral genome maintenance"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", while in HIV-1–like lentiviruses and unintegrated HIV-1, recruitment of Smc5/6 (directly or via accessory factors like SLF2) promotes chromatin compaction and epigenetic silencing of the viral genome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, selective binding to circular DNA and recognition of transcription‐induced positive supercoils further highlight its role in impeding viral transcription."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its antiviral functions, SMC6 is integral to maintaining genome integrity through its involvement in DNA repair and replication. Studies have shown that depletion of the Smc5/6 complex decreases sister chromatid homologous recombination, compromises the mitotic assembly of replicated chromosomes, and disrupts the proper resolution of topological stress during replication."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": " The SUMO ligase activity provided by the hMMS21 subunit modifies SMC6 and other DNA repair proteins, facilitating homologous recombination and proper repair of double-strand breaks."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Broader analyses and reviews further underscore the complex’s role in replication fork maintenance, coordination with topoisomerase IIα to resolve replication intermediates, participation in alternative telomere lengthening, and its essential requirement for cell viability by preventing spontaneous DNA damage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond DNA repair, the architectural features of the Smc5/6 complex are critical for higher‐order chromosome organization. Detailed structural studies reveal that SMC6, as part of a dynamic complex, contributes to the formation of toroidal, rod–like configurations with specialized “latch” and “hub” domains that are essential for linking DNA segments and promoting micro‐compaction. These structural insights, complemented by integrative reviews of interphase chromatin folding, underscore how the complex’s architecture enables it to manage DNA topology during transcription and facilitate proper chromosome segregation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Adrien Decorsière, Henrik Mueller, Pieter C van Breugel, et al. 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