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Up-Regulation of the Error-Prone DNA Polymerase Promotes Pleiotropic Genetic Alterations and Tumorigenesis

¹ Laboratory << Genetic instability and cancer >>, Institute of Pharmacology and Structural Biology, Centre National de la Recherche Scientifique, Toulouse, France; ² Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; ³ Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan; ⁴ Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton, United Kingdom; ⁵ FRE2584 Centre National de la Recherche Scientifique, Section Recherche, Institut Curie-Centre National de la Recherche Scientifique, Paris, France; ⁶ Institute for Cancer Studies, University of Sheffield, Medical School, Sheffield, United Kingdom; and ⁷ Division of Pathology, Chiba Cancer Center Research Institute, Chiba, Japan

Requests for reprints: Jean-Sébastien Hoffmann or Christophe Cazaux, Institute of Pharmacology and Structural Biology Centre National de la Recherche Scientifique UMR 5089, Supervision of the genome, de route de Narbonne, Toulouse, France, 31077. Phone: 356-117-5961; Fax: 356-117-5994; E-mail: jseb{at}ipbs.fr or cazaux{at}ipbs.fr.

It is currently widely accepted that genetic instability is key to cancer development. Many types of cancers arise as a consequence of a gradual accumulation of nucleotide aberrations, each mutation conferring growth and/or survival advantage. Genetic instability could also proceed in sudden bursts leading to a more drastic upheaval of structure and organization of the genome. Genetic instability, as an operative force, will produce genetic variants and the greater the instability, the larger the number of variants. We report here that the overexpression of human DNA polymerase , an error-prone enzyme that is up-regulated in lung cancers, induces DNA breaks and stimulates DNA exchanges as well as aneuploidy. Probably as the result of so many perturbations, excess polymerase favors the proliferation of competent tumor cells as observed in immunodeficient mice. These data suggest that altered regulation of DNA metabolism might be related to cancer-associated genetic changes and phenotype.

Key Words: Pol • mutagenesis • cancer • DNA recombination • DNA replication

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