Aneuploidy Affects Proliferation and Spontaneous Immortalization in Mammalian Cells

Aneuploidy, an incorrect number of chromosomes, is the leading cause of miscarriages and mental retardation in humans and is a hallmark of cancer. We examined the effects of aneuploidy on primary mouse cells by generating a series of cell lines that carry an extra copy of one of four mouse chromosomes. In all four trisomic lines, proliferation was impaired and metabolic properties were altered. Immortalization, the acquisition of the ability to proliferate indefinitely, was also affected by the presence of an additional copy of certain chromosomes. Our data indicate that aneuploidy decreases not only organismal but also cellular fitness and elicits traits that are shared between different aneuploid cells.

[1]  D. Borgaonkar,et al.  Handbook of Chromosomal Syndromes , 2002 .

[2]  Jonathan Pevsner,et al.  Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain. , 2003, Genomics.

[3]  Maitreya J. Dunham,et al.  Effects of Aneuploidy on Cellular Physiology and Cell Division in Haploid Yeast , 2007, Science.

[4]  E. Farber.  Clonal adaptation during carcinogenesis. , 1990, Biochemical pharmacology.

[5]  B. S. Baker,et al.  Segmental aneuploidy and the genetic gross structure of the Drosophila genome. , 1972, Genetics.

[6]  R. Lothe,et al.  Assessments of clonal composition of colorectal adenomas by FISH analysis of chromosomes 1, 7, 13 and 20 , 2001, International journal of cancer.

[7]  Richard P. Hill,et al.  The Basic Science of Oncology , 1989 .

[8]  Michael C. Ostrowski,et al.  Trisomy represses ApcMin-mediated tumours in mouse models of Down’s syndrome , 2008, Nature.

[9]  L. Cupples,et al.  Quantitative analysis of allele imbalance supports atypical ductal hyperplasia lesions as direct breast cancer precursors , 2006, The Journal of pathology.

[10]  V. Baranov,et al.  Cytogenetics of Mammalian Embryonic Development , 1988, Development.

[11]  S. Lowe,et al.  Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. , 2007, Cancer cell.

[12]  O. Niwa,et al.  Growth arrest and chromosome instability in aneuploid yeast , 2006, Yeast.

[13]  M. Abercrombie.  The bases of the locomotory behaviour of fibroblasts. , 1961, Experimental cell research.

[14]  P. Glazer,et al.  Decreased Expression of the DNA Mismatch Repair Gene Mlh1 under Hypoxic Stress in Mammalian Cells , 2003, Molecular and Cellular Biology.

[15]  H. Hasle,et al.  Risks of leukaemia and solid tumours in individuals with Down's syndrome , 2000, The Lancet.

[16]  Christian A. Ross,et al.  Roles of YqjH and YqjW, Homologs of the Escherichiacoli UmuC/DinB or Y Superfamily of DNA Polymerases, in Stationary-Phase Mutagenesis and UV-Induced Mutagenesis of Bacillussubtilis , 2003, Journal of bacteriology.

[17]  J. Berman,et al.  Aneuploidy and Isochromosome Formation in Drug-Resistant Candida albicans , 2006, Science.

[18]  S. Normark,et al.  Recombination between short DNA homologies causes tandem duplication , 1981, Nature.

[19]  A. Sasco,et al.  Are solid tumours different in children with Down's syndrome? , 2003, International journal of cancer.

[20]  O. Niwa,et al.  Triploid meiosis and aneuploidy in Schizosaccharomyces pombe: an unstable aneuploid disomic for chromosome III , 1985, Current Genetics.

[21]  Emma Saavedra,et al.  Energy metabolism in tumor cells , 2007, The FEBS journal.

[22]  A. Gropp,et al.  Systematic approach to the study of trisomy in the mouse. II. , 1975, Cytogenetics and cell genetics.

[23]  M. Rosner,et al.  Cell cycle and cell size regulation in Down syndrome cells. , 2003, Journal of neural transmission. Supplementum.

[24]  H. Winking,et al.  Murine trisomy: developmental profiles of the embryo, and isolation of trisomic cellular systems. , 1983, The Journal of experimental zoology.

[25]  D. Segal,et al.  Studies on Down's syndrome in tissue culture. I. Growth rates protein contents of fibroblast cultures , 1974, Journal of cellular physiology.

[26]  R. Kumar,et al.  BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice , 2004, Nature Genetics.

[27]  B. Mcclintock,et al.  A Cytological and Genetical Study of Triploid Maize. , 1929, Genetics.

[28]  K. Kinzler,et al.  Top-down morphogenesis of colorectal tumors , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[29]  H. Green,et al.  QUANTITATIVE STUDIES OF THE GROWTH OF MOUSE EMBRYO CELLS IN CULTURE AND THEIR DEVELOPMENT INTO ESTABLISHED LINES , 1963, The Journal of cell biology.

[30]  G. Khush,et al.  Secondary trisomics and telotrisomics of rice: origin, characterization, and use in determining the orientation of chromosome map. , 1996, Genetics.

[31]  M. Marcus,et al.  In vitro growth kinetics of mouse trisomies 12 and 19. , 2008, Hereditas.

[32]  M. Nishi,et al.  A tumor profile in Down syndrome. , 1998, American journal of medical genetics.

[33]  Cristina Montagna,et al.  Aneuploidy acts both oncogenically and as a tumor suppressor. , 2007, Cancer cell.

[34]  O. Kronborg,et al.  Cytogenetic analysis of colorectal adenomas: karyotypic comparisons of synchronous tumors. , 1998, Cancer genetics and cytogenetics.

[35]  S. Rosenberg,et al.  A switch from high-fidelity to error-prone DNA double-strand break repair underlies stress-induced mutation. , 2005, Molecular cell.