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Chemical-induced cancer incidence and underlying mechanisms in Fen1 mutant mice

Oncogene volume 30, pages 1072–1081 (2011)Cite this article

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Abstract

A critical observation in sporadic cancers is that not all individuals are equally prone to developing cancer following exposure to a given environmental carcinogen. Epidemiological studies have suggested that the difference in the timing of cancer onset in response to exogenous DNA damage is likely attributable to genetic variations, such as those associated with base excision repair (BER) genes. To test this long-standing hypothesis and elucidate how a genetic variation in the BER gene flap endonuclease 1 (FEN1) results in susceptibility to environment insults and causes cancer, we established a mutant mouse model carrying a point mutation (E160D) in Fen1. We demonstrate that the E160D mutation impairs the ability of FEN1 to process DNA intermediate structures in long-patch BER using nuclear extracts or reconstituted purified BER proteins. E160D cells were more sensitive to the base-damaging agents methylnitrosourea and hydrogen peroxide, leading to DNA strand breaks, chromosomal breakage and chromosome instabilities in response these DNA insults. We further show that E160D mice are significantly more susceptible to exposure to methylnitrosourea and develop lung adenocarcinoma. Thus, our current study demonstrates that a subtle genetic variation (E160D) in BER genes (FEN1) may cause a functional deficiency in repairing base damage, such that individuals carrying the mutation or similar mutations are predisposed to chemical-induced cancer development.

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Acknowledgements

We thank the microscopy core facility of City of Hope for technical assistance with immunofluorescence staining of MEF cells. We thank D Finger for technical advice on purification of FEN1 proteins. We thank SR da Costa and K Walker for editorial assistance. All protocols involving animal use were approved by the research animal care committee of City of Hope National Medical Center and Beckman Research Institute in compliance with the Public Health Service Policy on Use of Laboratory Animals. This work was supported by an NIH grant R01 CA073764 to BHS and a scholarship from China Scholarship Council (CSC) to HX.

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Authors and Affiliations

  1. Key Laboratory of Chinese Ministry of Agriculture for Nuclear-Agricultural Sciences, Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou, China

    H Xu, Y Hua & B Shen

  2. Department of Cancer Biology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA

    H Xu, L Zheng, H Dai, M Zhou & B Shen

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  1. H Xu
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  2. L Zheng
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  3. H Dai
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  4. M Zhou
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Correspondence to Y Hua or B Shen.

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Xu, H., Zheng, L., Dai, H. et al. Chemical-induced cancer incidence and underlying mechanisms in Fen1 mutant mice. Oncogene 30, 1072–1081 (2011). https://doi.org/10.1038/onc.2010.482

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