No cancer predisposition or increased spontaneous mutation frequencies in NEIL DNA glycosylases-deficient mice

Veslemøy Rolseth; Luisa Luna; Ann Karin Olsen; Rajikala Suganthan; Katja Scheffler; Christine G Neurauter; Ying Esbensen; Anna Kuśnierczyk; Gunn A Hildrestrand; Anne Graupner; Jill M Andersen; Geir Slupphaug; Arne Klungland; Hilde Nilsen; Magnar Bjørås

doi:10.1038/s41598-017-04472-4

No cancer predisposition or increased spontaneous mutation frequencies in NEIL DNA glycosylases-deficient mice

Sci Rep. 2017 Jun 29;7(1):4384. doi: 10.1038/s41598-017-04472-4.

Authors

Veslemøy Rolseth¹, Luisa Luna², Ann Karin Olsen³, Rajikala Suganthan⁴, Katja Scheffler⁵, Christine G Neurauter⁴, Ying Esbensen⁶, Anna Kuśnierczyk^{5

7}, Gunn A Hildrestrand⁴, Anne Graupner³, Jill M Andersen³, Geir Slupphaug^{5

7}, Arne Klungland⁴, Hilde Nilsen⁶, Magnar Bjørås^{8

9}

Affiliations

¹ Department of Microbiology, University of Oslo, Oslo University Hospital, Rikshospitalet, PO Box 4950 Nydalen, N-0424, Oslo, Norway. vesrol@ous-hf.no.
² Department of Microbiology, University of Oslo, Oslo University Hospital, Rikshospitalet, PO Box 4950 Nydalen, N-0424, Oslo, Norway. luisa.luna@rr-research.no.
³ Centre of Environmental Radioactivity (CERAD CoE), Norway and Department of Molecular Biology, Norwegian Institute of Public Health, Oslo, Norway.
⁴ Department of Microbiology, University of Oslo, Oslo University Hospital, Rikshospitalet, PO Box 4950 Nydalen, N-0424, Oslo, Norway.
⁵ Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491, Trondheim, Norway.
⁶ Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Nordbyhagen, 1474, Norway.
⁷ The Proteomics and Metabolomics Core Facility (PROMEC), Norwegian University of Science and Technology, 7491, Trondheim, Norway.
⁸ Department of Microbiology, University of Oslo, Oslo University Hospital, Rikshospitalet, PO Box 4950 Nydalen, N-0424, Oslo, Norway. magnar.bjoras@rr-research.no.
⁹ Institute of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491, Trondheim, Norway. magnar.bjoras@rr-research.no.

Abstract

Base excision repair (BER) is a major pathway for removal of DNA base lesions and maintenance of genomic stability, which is essential in cancer prevention. DNA glycosylases recognize and remove specific lesions in the first step of BER. The existence of a number of these enzymes with overlapping substrate specificities has been thought to be the reason why single knock-out models of individual DNA glycosylases are not cancer prone. In this work we have characterized DNA glycosylases NEIL1 and NEIL2 (Neil1 ^-/- /Neil2 ^-/-) double and NEIL1, NEIL2 and NEIL3 (Neil1 ^-/- /Neil2 ^-/- /Neil3 ^-/-) triple knock-out mouse models. Unexpectedly, our results show that these mice are not prone to cancer and have no elevated mutation frequencies under normal physiological conditions. Moreover, telomere length is not affected and there was no accumulation of oxidative DNA damage compared to wild-type mice. These results strengthen the hypothesis that the NEIL enzymes are not simply back-up enzymes for each other but enzymes that have distinct functions beyond canonical repair.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
DNA Glycosylases / deficiency*
Disease Models, Animal
Genetic Association Studies
Genetic Loci
Genetic Predisposition to Disease*
Hydrogen Peroxide / pharmacology
Mice
Mice, Knockout
Multigene Family
Mutation Rate*
Mutation*
Neoplasms / genetics*
Neoplasms / metabolism
Neoplasms / pathology
Potassium Dichromate / pharmacology

Substances

Hydrogen Peroxide
DNA Glycosylases
Potassium Dichromate

Grants and funding

R44 ES018017/ES/NIEHS NIH HHS/United States