Fen1 mutations result in autoimmunity, chronic inflammation and cancers

Li Zheng, Huifang Dai, Mian Zhou, Mei Li, Purnima Singh, Junzhuan Qiu, Walter Tsark, Qin Huang, Kemp Kernstine, Xuemei Zhang, Dongxin Lin, Binghui Shen

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Functional deficiency of the FEN1 gene has been suggested to cause genomic instability and cancer predisposition. We have identified a group of FEN1 mutations in human cancer specimens. Most of these mutations abrogated two of three nuclease activities of flap endonuclease 1 (FEN1). To demonstrate the etiological significance of these somatic mutations, we inbred a mouse line harboring the E160D mutation representing mutations identified in human cancers. Selective elimination of nuclease activities led to frequent spontaneous mutations and accumulation of incompletely digested DNA fragments in apoptotic cells. The mutant mice were predisposed to autoimmunity, chronic inflammation and cancers. The mutator phenotype results in the initiation of cancer, whereas chronic inflammation promotes the cancer progression. The current work exemplifies the approach of studying the mechanisms of individual polymorphisms and somatic mutations in cancer development, and may serve as a reference in developing new therapeutic regimens through the suppression of inflammatory responses.

Original languageEnglish (US)
Pages (from-to)812-819
Number of pages8
JournalNature Medicine
Volume13
Issue number7
DOIs
StatePublished - Jul 2007

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Flap Endonucleases
Autoimmunity
Inflammation
Mutation
Neoplasms
Polymorphism
Genes
Cells
DNA
Genomic Instability
Phenotype

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Zheng, L., Dai, H., Zhou, M., Li, M., Singh, P., Qiu, J., ... Shen, B. (2007). Fen1 mutations result in autoimmunity, chronic inflammation and cancers. Nature Medicine, 13(7), 812-819. https://doi.org/10.1038/nm1599

Fen1 mutations result in autoimmunity, chronic inflammation and cancers. / Zheng, Li; Dai, Huifang; Zhou, Mian; Li, Mei; Singh, Purnima; Qiu, Junzhuan; Tsark, Walter; Huang, Qin; Kernstine, Kemp; Zhang, Xuemei; Lin, Dongxin; Shen, Binghui.

In: Nature Medicine, Vol. 13, No. 7, 07.2007, p. 812-819.

Research output: Contribution to journalArticle

Zheng, L, Dai, H, Zhou, M, Li, M, Singh, P, Qiu, J, Tsark, W, Huang, Q, Kernstine, K, Zhang, X, Lin, D & Shen, B 2007, 'Fen1 mutations result in autoimmunity, chronic inflammation and cancers', Nature Medicine, vol. 13, no. 7, pp. 812-819. https://doi.org/10.1038/nm1599
Zheng L, Dai H, Zhou M, Li M, Singh P, Qiu J et al. Fen1 mutations result in autoimmunity, chronic inflammation and cancers. Nature Medicine. 2007 Jul;13(7):812-819. https://doi.org/10.1038/nm1599
Zheng, Li ; Dai, Huifang ; Zhou, Mian ; Li, Mei ; Singh, Purnima ; Qiu, Junzhuan ; Tsark, Walter ; Huang, Qin ; Kernstine, Kemp ; Zhang, Xuemei ; Lin, Dongxin ; Shen, Binghui. / Fen1 mutations result in autoimmunity, chronic inflammation and cancers. In: Nature Medicine. 2007 ; Vol. 13, No. 7. pp. 812-819.
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