title: Characterization of a natural mutator variant of human DNA polymerase lambda which promotes chromosomal instability by compromising NHEJ.
abstract: BACKGROUND
  DNA polymerase lambda (Pollambda) is a DNA repair polymerase, which likely plays a role in base excision repair (BER) and in non-homologous end joining (NHEJ) of DNA double-strand breaks (DSB).
  
  
  RESULTS
  Here, we described a novel natural allelic variant of human Pollambda (hPollambda) characterized by a single nucleotide polymorphism (SNP), C/T variation in the first base of codon 438, resulting in the amino acid change Arg to Trp. In vitro enzyme activity assays of the purified W438 Pollambda variant revealed that it retained both DNA polymerization and deoxyribose phosphate (dRP) lyase activities, but had reduced base substitution fidelity. Ectopic expression of the W438 hPollambda variant in mammalian cells increases mutation frequency, affects the DSB repair NHEJ pathway, and generates chromosome aberrations. All these phenotypes are dependent upon the catalytic activity of the W438 hPollambda.
  
  
  CONCLUSIONS
  The expression of a cancer-related natural variant of one specialized DNA polymerase can be associated to generic instability at the cromosomal level, probably due a defective NHEJ. These results establish that chromosomal aberrations can result from mutations in specialized DNA repair polymerases.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Terrados
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Capp
authors.forename: Yvan
authors.initials: Y
authors.lastname: Canitrot
authors.forename: Miguel
authors.initials: M
authors.lastname: García-Díaz
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bebenek
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhoff
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.forename: François
authors.initials: F
authors.lastname: Boudsocq
authors.forename: Valérie
authors.initials: V
authors.lastname: Bergoglio
authors.forename: Christophe
authors.initials: C
authors.lastname: Cazaux
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kunkel
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hoffmann
authors.forename: Luis
authors.initials: L
authors.lastname: Blanco
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D001120:Arginine / Q000737:chemistry; D043171:Chromosomal Instability / Q000235:genetics*; D002869:Chromosome Aberrations; D003062:Codon; D004247:DNA / Q000737:chemistry; D053903:DNA Breaks, Double-Stranded; D004252:DNA Mutational Analysis; D019951:DNA Polymerase beta / Q000235:genetics* / Q000502:physiology; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D014364:Tryptophan / Q000737:chemistry
chemical_list: D000596:Amino Acids; D003062:Codon; D004268:DNA-Binding Proteins; C508551:NHEJ1 protein, human; D014364:Tryptophan; D004247:DNA; D001120:Arginine; C415367:DNA polymerase beta2; D019951:DNA Polymerase beta; D045643:DNA Repair Enzymes