{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nZSCAN4 is a critical factor transiently expressed in embryonic stem cells and early embryos where it ensures genomic stability through multiple mechanisms. In this context, ZSCAN4 promotes telomere elongation and maintains proper chromosomal end‐protection by directly associating with shelterin components such as Rap1 and potentially TRF1, thereby safeguarding telomere length homeostasis. Its expression is exquisitely regulated, as evidenced by a rapid turnover mediated via lysine‐48–linked polyubiquitination and RNF20‐dependent proteasome degradation. In addition, ZSCAN4 is expressed in adult gonads, with dynamic localization patterns in oocytes and spermatocytes correlating with key transitions during meiotic prophase."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the arena of DNA damage response and tumor biology, ZSCAN4 plays multifaceted roles. It is induced during the acute DNA damage response via an ATM‐TRAF6‐TAK1 signaling cascade, which enables a long‑term senescence‑associated secretory phenotype (SASP) in treatment‑damaged stromal cells. In head and neck squamous cell carcinoma, transient ZSCAN4 expression enriches cancer stem cell populations by upregulating pluripotency markers and driving epigenetic alterations (including enhanced histone H3 acetylation). Moreover, altered ZSCAN4 expression—in particular its downregulation in muscle‐invasive bladder cancer—points to its context‑dependent impact on tumor aggressiveness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in telomere biology and cancer, ZSCAN4 exerts regulatory influence at the chromatin level. Genome‑wide binding studies have revealed that ZSCAN4 recognizes specific microsatellite sequences—particularly those capable of forming Z‑DNA—thereby contributing to chromatin suppression and the prevention of deleterious DNA breaks. In addition, members of the ZSCAN4 family, such as ZSCAN4f, recruit the DNA dioxygenase Tet2 via their SCAN domains, which promotes DNA demethylation and facilitates metabolic rewiring during cell reprogramming. Together, these molecular interactions underscore ZSCAN4’s central role in re‐programming chromatin states and preserving genome integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kyungwoo Lee, Lauren S Gollahon "}, {"type": "b", "children": [{"type": "t", "text": "Zscan4 interacts directly with human Rap1 in cancer cells regardless of telomerase status."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cbt.29220"}], "href": "https://doi.org/10.4161/cbt.29220"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24840609"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24840609"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kyungwoo Lee, Lauren S Gollahon "}, {"type": "b", "children": [{"type": "t", "text": "ZSCAN4 and TRF1: A functionally indirect interaction in cancer cells independent of telomerase activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2015.09.107"}], "href": "https://doi.org/10.1016/j.bbrc.2015.09.107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26403970"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26403970"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kei-Ichiro Ishiguro, Yuhki Nakatake, Nana Chikazawa-Nohtomi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression analysis of the endogenous Zscan4 locus and its coding proteins in mouse ES cells and preimplantation embryos."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "In Vitro Cell Dev Biol Anim (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11626-016-0097-y"}], "href": "https://doi.org/10.1007/s11626-016-0097-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27699651"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27699651"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kei-Ichiro Ishiguro, Manuela Monti, Tomohiko Akiyama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Zscan4 is expressed specifically during late meiotic prophase in both spermatogenesis and oogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "In Vitro Cell Dev Biol Anim (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11626-016-0096-z"}], "href": "https://doi.org/10.1007/s11626-016-0096-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27699653"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27699653"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Benjamin A Portney, Raju Khatri, W Alex Meltzer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZSCAN4 is negatively regulated by the ubiquitin-proteasome system and the E3 ubiquitin ligase RNF20."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2018.02.155"}], "href": "https://doi.org/10.1016/j.bbrc.2018.02.155"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29477841"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29477841"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Boyi Zhang, Da Fu, Qixia Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-018-04010-4"}], "href": "https://doi.org/10.1038/s41467-018-04010-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29712904"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29712904"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Benjamin A Portney, Michal Arad, Aditi Gupta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZSCAN4 facilitates chromatin remodeling and promotes the cancer stem cell phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41388-020-1333-1"}], "href": "https://doi.org/10.1038/s41388-020-1333-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32507861"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32507861"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Hong-Lin He, Hong-Yue Lai, Ti-Chun Chan, et al. 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