{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSTAG2 is a core subunit of the cohesin complex that plays a key role in maintaining proper sister chromatid cohesion and in regulating three‐dimensional chromatin organization that underlies gene expression. Biochemical studies have shown that complexes containing STAG2 (also known as the SA2 subunit) participate in the precise control of centromeric cohesion during mitosis, contribute to chromatin insulation via direct interaction with factors such as CTCF, and even act as transcriptional co‐activators at select promoters. These findings collectively underscore the fundamental role of STAG2 in ensuring genome stability and proper gene regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer settings, inactivating mutations or loss of expression of STAG2 have been reported across a wide spectrum of tumor types—including Ewing sarcoma, urothelial bladder cancer, glioblastoma, and myeloid malignancies—where such alterations are often associated with chromosomal mis-segregation, aneuploidy, and deregulated transcriptional programs. Loss of STAG2 function in these tumors not only correlates with poorer outcomes and disease dissemination but also impacts cellular differentiation and self-renewal in hematopoietic progenitors. Furthermore, studies using immunohistochemical and genomic analyses have identified recurrent STAG2 alterations that, in certain contexts, appear to influence therapeutic response and disease progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional investigations have revealed therapeutic vulnerabilities stemming from STAG2 loss. In tumor cells deficient for STAG2, synthetic lethal interactions emerge with its paralog STAG1, rendering these cancers particularly sensitive to STAG1 inhibition—a finding that may be harnessed for targeted therapies. Moreover, STAG2 inactivation disrupts enhancer–promoter looping and replication fork progression, thereby sensitizing cells to DNA-damaging agents and PARP inhibitors, while also eliciting aberrant interferon responses that can broadly affect viral replication. These insights into the altered chromatin architecture, DNA repair deficits, and synthetic lethality associated with STAG2 loss provide a strong rationale for the development of novel, selective therapeutic strategies against STAG2-mutated cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Enrique Lara-Pezzi, Nieves Pezzi, Ignacio Prieto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evidence of a transcriptional co-activator function of cohesin STAG/SA/Scc3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M307663200"}], "href": "https://doi.org/10.1074/jbc.M307663200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14660624"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14660624"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Silvia Canudas, Susan Smith "}, {"type": "b", "children": [{"type": "t", "text": "Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2, respectively, in human cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200903096"}], "href": "https://doi.org/10.1083/jcb.200903096"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19822671"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19822671"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Tiaojiang Xiao, Julie Wallace, Gary Felsenfeld "}, {"type": "b", "children": [{"type": "t", "text": "Specific sites in the C terminus of CTCF interact with the SA2 subunit of the cohesin complex and are required for cohesin-dependent insulation activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.05093-11"}], "href": "https://doi.org/10.1128/MCB.05093-11"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21444719"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21444719"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "David A Solomon, Taeyeon Kim, Laura A Diaz-Martinez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutational inactivation of STAG2 causes aneuploidy in human cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1203619"}], "href": "https://doi.org/10.1126/science.1203619"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21852505"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21852505"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "David A Solomon, Jung-Sik Kim, Jolanta Bondaruk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Frequent truncating mutations of STAG2 in bladder cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.2800"}], "href": "https://doi.org/10.1038/ng.2800"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24121789"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24121789"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Claire F Taylor, Fiona M Platt, Carolyn D Hurst, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Frequent inactivating mutations of STAG2 in bladder cancer are associated with low tumour grade and stage and inversely related to chromosomal copy number changes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddt589"}], "href": "https://doi.org/10.1093/hmg/ddt589"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24270882"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24270882"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Felicitas Thol, Robin Bollin, Marten Gehlhaar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2013-07-518746"}], "href": "https://doi.org/10.1182/blood-2013-07-518746"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24335498"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24335498"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Andrew S Brohl, David A Solomon, Wendy Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1004475"}], "href": "https://doi.org/10.1371/journal.pgen.1004475"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25010205"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25010205"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Brian D Crompton, Chip Stewart, Amaro Taylor-Weiner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The genomic landscape of pediatric Ewing sarcoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Discov (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/2159-8290.CD-13-1037"}], "href": "https://doi.org/10.1158/2159-8290.CD-13-1037"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25186949"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25186949"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Franck Tirode, Didier Surdez, Xiaotu Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Discov (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/2159-8290.CD-14-0622"}], "href": "https://doi.org/10.1158/2159-8290.CD-14-0622"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25223734"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25223734"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Victoria K Hill, Jung-Sik Kim, Todd Waldman "}, {"type": "b", "children": [{"type": "t", "text": "Cohesin mutations in human cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbcan.2016.05.002"}], "href": "https://doi.org/10.1016/j.bbcan.2016.05.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27207471"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27207471"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Che-Hung Shen, Sun Hye Kim, Sebastian Trousil, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.4155"}], "href": "https://doi.org/10.1038/nm.4155"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27500726"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27500726"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Sureni V Mullegama, Steven D Klein, Milene V Mulatinho, et al. "}, {"type": "b", "children": [{"type": "t", "text": "De novo loss-of-function variants in STAG2 are associated with developmental delay, microcephaly, and congenital anomalies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.38207"}], "href": "https://doi.org/10.1002/ajmg.a.38207"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28296084"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28296084"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Alana Lelo, Frederik Prip, Brent T Harris, et al. "}, {"type": "b", "children": [{"type": "t", "text": "STAG2 Is a Biomarker for Prediction of Recurrence and Progression in Papillary Non-Muscle-Invasive Bladder Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-17-3244"}], "href": "https://doi.org/10.1158/1078-0432.CCR-17-3244"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29954776"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29954776"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Aaron D Viny, Robert L Bowman, Yu Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cohesin Members Stag1 and Stag2 Display Distinct Roles in Chromatin Accessibility and Topological Control of HSC Self-Renewal and Differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Stem Cell (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stem.2019.08.003"}], "href": "https://doi.org/10.1016/j.stem.2019.08.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31495782"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31495782"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Ana Cuadrado, Ana Losada "}, {"type": "b", "children": [{"type": "t", "text": "Specialized functions of cohesins STAG1 and STAG2 in 3D genome architecture."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Opin Genet Dev (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gde.2020.02.024"}], "href": "https://doi.org/10.1016/j.gde.2020.02.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32294612"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32294612"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Elvin Wagenblast, Joana Araújo, Olga I Gan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mapping the cellular origin and early evolution of leukemia in Down syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.abf6202"}], "href": "https://doi.org/10.1126/science.abf6202"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34244384"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34244384"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Melanie L Bailey, Nigel J O'Neil, Derek M van Pel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glioblastoma cells containing mutations in the cohesin component STAG2 are sensitive to PARP inhibition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Ther (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1535-7163.MCT-13-0749"}], "href": "https://doi.org/10.1158/1535-7163.MCT-13-0749"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24356817"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24356817"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Petra van der Lelij, Simone Lieb, Julian Jude, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Synthetic lethality between the cohesin subunits "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "STAG1"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " and "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "STAG2"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " in diverse cancer contexts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.26980"}], "href": "https://doi.org/10.7554/eLife.26980"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28691904"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28691904"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Siyuan Ding, Jonathan Diep, Ningguo Feng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "STAG2 deficiency induces interferon responses via cGAS-STING pathway and restricts virus infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-018-03782-z"}], "href": "https://doi.org/10.1038/s41467-018-03782-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29662124"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29662124"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Petra van der Lelij, Joseph A Newman, Simone Lieb, et al. "}, {"type": "b", "children": [{"type": "t", "text": "STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Life Sci Alliance (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.26508/lsa.202000725"}], "href": "https://doi.org/10.26508/lsa.202000725"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32467316"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32467316"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "James S Smith, Katrina M Lappin, Stephanie G Craig, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Chronic loss of STAG2 leads to altered chromatin structure contributing to de-regulated transcription in AML."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Transl Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12967-020-02500-y"}], "href": "https://doi.org/10.1186/s12967-020-02500-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32883299"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32883299"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Didier Surdez, Sakina Zaidi, Sandrine Grossetête, et al. "}, {"type": "b", "children": [{"type": "t", "text": "STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Cell (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ccell.2021.04.001"}], "href": "https://doi.org/10.1016/j.ccell.2021.04.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33930311"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33930311"}]}]}]}