Up-regulation of the error-prone DNA polymerase {kappa} promotes pleiotropic genetic alterations and tumorigenesis.
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 kappa, 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 kappa 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.
Bavoux
Clarisse
C
Institute of Pharmacology and Structural Biology, Centre National de la Recherche Scientifique, Toulouse, France.
Leopoldino
Andréia Machado
AM
Bergoglio
Valérie
V
O-Wang
Jiyang
J
Ogi
Tomoo
T
Bieth
Anne
A
Judde
Jean-Gabriel
JG
Pena
Sérgio Danilo Junho
SD
Poupon
Marie-France
MF
Helleday
Thomas
T
Tagawa
Masatoshi
M
Machado
Carlosrenato
C
Hoffmann
Jean-Sébastien
JS
Cazaux
Christophe
C
D000782:Aneuploidy; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002874:Chromosome Mapping; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D005787:Gene Frequency; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics; D011995:Recombination, Genetic; D000099270:Y-Family DNA Polymerases
D004259:DNA-Directed DNA Polymerase; C404302:POLK protein, human; D000099270:Y-Family DNA Polymerases