Mutation frequencies and spectra in DNA polymerase η-deficient mice

Rita A. Busuttil, Qingcong Lin, Peter J. Stambrook, Raju Kucherlapati, Jan Vijg

Research output: Contribution to journalArticle

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Abstract

The low-fidelity polymerase η (polη) is required for bypass of UV-induced pyrimidine dimers inserting adenine nucleotides opposite these lesions. Mutations in the polη gene are responsible for the genetic defect in xeroderma pigmentosum variant patients. To study if the lackof polη significantly elevates spontaneous mutation frequency in various organs and tissues of the mouse, we crossed polη-deficient mice with transgenic mice harboring a chromosomally integrated lacZ-plasmid reporter construct. In cultured embryonic fibroblasts from the lacZ-polη-/- mice, 2.5 J/m2 UV irradiation induced ∼5-fold more mutations than in cells from lacZ control mice, in which an ∼3-fold increase in mutation frequency was found compared with the normal level. Whereas untreated cells harbored mainly 1-bp deletions, UV induced both transitions and transversions, with the latter type more highly represented in the polη-null cells than in the controls. No difference in mutation induction between the polH-null cells and the wild-type cells was observed after treatment with N-ethyl-N-nitrosourea. Having shown the validity of the lacZ model to accurately identify polη-associated mutagenesis, we then determined the mutant frequency at the lacZ locus in liver, spleen, and small intestine of 12-month-old animals. No differences were found between polη-null, heterozygous, or littermate control mice. We conclude that the polη defect is specific for UV damage and has no effect on in vivo mutagenesis in mice.

Original languageEnglish (US)
Pages (from-to)2081-2084
Number of pages4
JournalCancer Research
Volume68
Issue number7
DOIs
StatePublished - Apr 1 2008
Externally publishedYes

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Mutation Rate
DNA-Directed DNA Polymerase
Null Lymphocytes
Mutagenesis
Mutation
Ethylnitrosourea
Pyrimidine Dimers
Adenine Nucleotides
Transgenic Mice
Small Intestine
Plasmids
Spleen
Fibroblasts
Liver
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mutation frequencies and spectra in DNA polymerase η-deficient mice. / Busuttil, Rita A.; Lin, Qingcong; Stambrook, Peter J.; Kucherlapati, Raju; Vijg, Jan.

In: Cancer Research, Vol. 68, No. 7, 01.04.2008, p. 2081-2084.

Research output: Contribution to journalArticle

Busuttil, RA, Lin, Q, Stambrook, PJ, Kucherlapati, R & Vijg, J 2008, 'Mutation frequencies and spectra in DNA polymerase η-deficient mice', Cancer Research, vol. 68, no. 7, pp. 2081-2084. https://doi.org/10.1158/0008-5472.CAN-07-6274
Busuttil, Rita A. ; Lin, Qingcong ; Stambrook, Peter J. ; Kucherlapati, Raju ; Vijg, Jan. / Mutation frequencies and spectra in DNA polymerase η-deficient mice. In: Cancer Research. 2008 ; Vol. 68, No. 7. pp. 2081-2084.
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