title: Intact Cohesion, Anaphase, and Chromosome Segregation in Human Cells Harboring Tumor-Derived Mutations in STAG2.
abstract: Somatic mutations of the cohesin complex subunit STAG2 are present in diverse tumor types. We and others have shown that STAG2 inactivation can lead to loss of sister chromatid cohesion and alterations in chromosome copy number in experimental systems. However, studies of naturally occurring human tumors have demonstrated little, if any, correlation between STAG2 mutational status and aneuploidy, and have further shown that STAG2-deficient tumors are often euploid. In an effort to provide insight into these discrepancies, here we analyze the effect of tumor-derived STAG2 mutations on the protein composition of cohesin and the expected mitotic phenotypes of STAG2 mutation. We find that many mutant STAG2 proteins retain their ability to interact with cohesin; however, the presence of mutant STAG2 resulted in a reduction in the ability of regulatory subunits WAPL, PDS5A, and PDS5B to interact with the core cohesin ring. Using AAV-mediated gene targeting, we then introduced nine tumor-derived mutations into the endogenous allele of STAG2 in cultured human cells. While all nonsense mutations led to defects in sister chromatid cohesion and a subset induced anaphase defects, missense mutations behaved like wild-type in these assays. Furthermore, only one of nine tumor-derived mutations tested induced overt alterations in chromosome counts. These data indicate that not all tumor-derived STAG2 mutations confer defects in cohesion, chromosome segregation, and ploidy, suggesting that there are likely to be other functional effects of STAG2 inactivation in human cancer cells that are relevant to cancer pathogenesis.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, D.C, United States of America.
authors.forename: Jung-Sik
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, D.C, United States of America.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Orr
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna, Austria.
authors.forename: Gordana
authors.initials: G
authors.lastname: Wutz
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, D.C, United States of America.
authors.forename: Victoria
authors.initials: V
authors.lastname: Hill
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna, Austria.
authors.forename: Jan-Michael
authors.initials: JM
authors.lastname: Peters
authors.affiliation: Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
authors.forename: Duane A
authors.initials: DA
authors.lastname: Compton
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, D.C, United States of America.
authors.forename: Todd
authors.initials: T
authors.lastname: Waldman
mesh_terms: D000705:Anaphase; D034961:Antigens, Nuclear / Q000235:genetics*; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002842:Chromatids / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D020090:Chromosome Segregation; D002877:Chromosomes, Human / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics; D000229:Dependovirus / Q000378:metabolism; D018390:Gene Targeting; D045325:HCT116 Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D018389:Codon, Nonsense; D021122:Protein Subunits; D000097722:Cohesins; C508565:STAG2 protein, human