title: The presence of extra chromosomes leads to genomic instability.
abstract: Aneuploidy is a hallmark of cancer and underlies genetic disorders characterized by severe developmental defects, yet the molecular mechanisms explaining its effects on cellular physiology remain elusive. Here we show, using a series of human cells with defined aneuploid karyotypes, that gain of a single chromosome increases genomic instability. Next-generation sequencing and SNP-array analysis reveal accumulation of chromosomal rearrangements in aneuploids, with break point junction patterns suggestive of replication defects. Trisomic and tetrasomic cells also show increased DNA damage and sensitivity to replication stress. Strikingly, we find that aneuploidy-induced genomic instability can be explained by the reduced expression of the replicative helicase MCM2-7. Accordingly, restoring near-wild-type levels of chromatin-bound MCM helicase partly rescues the genomic instability phenotypes. Thus, gain of chromosomes triggers replication stress, thereby promoting genomic instability and possibly contributing to tumorigenesis.
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried 82152, Germany.|Center for Integrated Protein Science Munich, Munich, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Passerini
authors.affiliation: Department of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, Givat-Ram, Jerusalem 91904, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Ozeri-Galai
authors.affiliation: Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, Utrecht 3584 CG, The Netherlands.
authors.forename: Mirjam S
authors.initials: MS
authors.lastname: de Pagter
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried 82152, Germany.
authors.forename: Neysan
authors.initials: N
authors.lastname: Donnelly
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried 82152, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schmalbrock
authors.affiliation: Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, Utrecht 3584 CG, The Netherlands.
authors.forename: Wigard P
authors.initials: WP
authors.lastname: Kloosterman
authors.affiliation: Department of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, Givat-Ram, Jerusalem 91904, Israel.
authors.forename: Batsheva
authors.initials: B
authors.lastname: Kerem
authors.affiliation: Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried 82152, Germany.|Center for Integrated Protein Science Munich, Munich, Germany.|Technical University Kaiserslautern, Paul-Ehrlich Strasse, Building 24, Kaiserslautern 67663, Germany.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Storchová
mesh_terms: D000782:Aneuploidy; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004247:DNA / Q000096:biosynthesis*; D005455:Fluorescent Antibody Technique; D042822:Genomic Instability / Q000235:genetics*; D045325:HCT116 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008677:Metaphase / Q000235:genetics*; D018613:Microscopy, Confocal; D064110:Minichromosome Maintenance Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D058670:Tetrasomy / Q000235:genetics*; D014314:Trisomy / Q000235:genetics*
chemical_list: D004247:DNA; D064110:Minichromosome Maintenance Proteins