title: Antagonizing functions of BARD1 and its alternatively spliced variant BARD1δ in telomere stability.
abstract: Previous reports have shown that expression of BARD1δ, a deletion-bearing isoform of BARD1, correlates with tumor aggressiveness and progression. We show that expression of BARD1δ induces cell cycle arrest in vitro and in vivo in non-malignant cells. We investigated the mechanism that leads to proliferation arrest and found that BARD1δ overexpression induced mitotic arrest with chromosome and telomere aberrations in cell cultures, in transgenic mice, and in cells from human breast and ovarian cancer patients with BARD1 mutations. BARD1δ binds more efficiently than BARD1 to telomere binding proteins and causes their depletion from telomeres, leading to telomere and chromosomal instability. While this induces cell cycle arrest, cancer cells lacking G2/M checkpoint controls might continue to proliferate despite the BARD1δ-induced chromosomal instability. These features of BARD1δ may make it a genome permutator and a driver of continuous uncontrolled proliferation of cancer cells.
authors.affiliation: Department of Gynecology and Obstetrics Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Maxim
authors.initials: M
authors.lastname: Pilyugin
authors.affiliation: Department of Gynecology and Obstetrics Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: André
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Poland.|Centre for Cell Therapy and Regenerative Medicine, University of Western Australia and Institute of Respiratory Health, Nedlands, Australia.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ratajska
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Poland.
authors.forename: Alina
authors.initials: A
authors.lastname: Kuzniacka
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Limon
authors.affiliation: Department of Neuropsychiatry, Vulnerability Biomarkers Unit, University Hospital of Geneva, Geneva, Switzerland.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Tournier
authors.affiliation: Department of Gynecology and Obstetrics Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Colas
authors.affiliation: Centre for Cell Therapy and Regenerative Medicine, University of Western Australia and Institute of Respiratory Health, Nedlands, Australia.
authors.forename: Geoff
authors.initials: G
authors.lastname: Laurent
authors.affiliation: Department of Gynecology and Obstetrics Geneva University Hospitals, Geneva, Switzerland.|Centre for Cell Therapy and Regenerative Medicine, University of Western Australia and Institute of Respiratory Health, Nedlands, Australia.|Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Irminger-Finger
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D043171:Chromosomal Instability; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D020033:Protein Isoforms; D000089804:Shelterin Complex; D015398:Signal Transduction; D016615:Telomere / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059505:Telomere Homeostasis; D034501:Telomere-Binding Proteins / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D020033:Protein Isoforms; D000089804:Shelterin Complex; C504753:TERF2 protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: BARD1; alternative splicing; genome permutator; shelterin; telomere alteration