title: Whole Chromosome Instability induces senescence and promotes SASP.
abstract: Age-related accumulation of ploidy changes is associated with decreased expression of genes controlling chromosome segregation and cohesin functions. To determine the consequences of whole chromosome instability (W-CIN) we down-regulated the spindle assembly checkpoint component BUB1 and the mitotic cohesin SMC1A, and used four-color-interphase-FISH coupled with BrdU incorporation and analyses of senescence features to reveal the fate of W-CIN cells. We observed significant correlations between levels of not-diploid cells and senescence-associated features (SAFs). W-CIN induced DNA double strand breaks and elevated oxidative stress, but caused low apoptosis. SAFs of W-CIN cells were remarkably similar to those induced by replicative senescence but occurred in only 13 days versus 4 months. Cultures enriched with not-diploid cells acquired a senescence-associated secretory phenotype (SASP) characterized by IL1B, CXCL8, CCL2, TNF, CCL27 and other pro-inflammatory factors including a novel SASP component CLEC11A. These findings suggest that W-CIN triggers premature senescence, presumably to prevent the propagation of cells with an abnormal DNA content. Cells deviating from diploidy have the ability to communicate with their microenvironment by secretion of an array of signaling factors. Our results suggest that aneuploid cells that accumulate during aging in some mammalian tissues potentially contribute to age-related pathologies and inflammation through SASP secretion.
authors.affiliation: Departments of Genetics, Albert Einstein College of Medicine, New York, United States.
authors.forename: Grasiella Angelina
authors.initials: GA
authors.lastname: Andriani
authors.affiliation: Institute of Tropical Pathology and Public Health, Federal University of Goias (UFG), Goiania, GO, Brazil.
authors.forename: Vinnycius Pereira
authors.initials: VP
authors.lastname: Almeida
authors.affiliation: Departments of Genetics, Albert Einstein College of Medicine, New York, United States.
authors.forename: Francesca
authors.initials: F
authors.lastname: Faggioli
authors.affiliation: Departments of Genetics, Albert Einstein College of Medicine, New York, United States.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Mauro
authors.affiliation: Translational Immunology Section, Office of Science and Technology, National Institute of Arthritis Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Wanxia Li
authors.initials: WL
authors.lastname: Tsai
authors.affiliation: Pathology, Albert Einstein College of Medicine, New York, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Santambrogio
authors.affiliation: Departments of Genetics, Albert Einstein College of Medicine, New York, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Maslov
authors.affiliation: Translational Immunology Section, Office of Science and Technology, National Institute of Arthritis Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Gadina
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, California, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
authors.affiliation: Departments of Genetics, Albert Einstein College of Medicine, New York, United States.|Ophthalmology and Visual Science, Albert Einstein College of Medicine, New York, United States.|Obstetrics &Gynecology and Women's Health, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Vijg
authors.affiliation: Departments of Genetics, Albert Einstein College of Medicine, New York, United States.|Pathology, Albert Einstein College of Medicine, New York, United States.
authors.forename: Cristina
authors.initials: C
authors.lastname: Montagna
mesh_terms: D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D043171:Chromosomal Instability; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D055785:Gene Knockdown Techniques; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000098550:Structural Maintenance of Chromosome Protein 1; D017346:Protein Serine-Threonine Kinases