Article abstract
Nature Medicine 13, 812 - 819 (2007)
Published online: 24 June 2007 | doi:10.1038/nm1599
Fen1 mutations result in autoimmunity, chronic inflammation and cancers
Li Zheng1, Huifang Dai1, Mian Zhou1, Mei Li1, Purnima Singh1, Junzhuan Qiu1, Walter Tsark2, Qin Huang3, Kemp Kernstine4, Xuemei Zhang5, Dongxin Lin5 & Binghui Shen1
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.
- Department of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute, 1500 East Duarte Road, Duarte, California 91010, USA.
- Division of Biology, City of Hope National Medical Center and Beckman Research Institute, 1500 East Duarte Road, Duarte, California 91010, USA.
- Division of Pathology, City of Hope National Medical Center and Beckman Research Institute, 1500 East Duarte Road, Duarte, California 91010, USA.
- Division of Surgery, City of Hope National Medical Center and Beckman Research Institute, 1500 East Duarte Road, Duarte, California 91010, USA.
- Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences, 17 Panjiayan Nanli, Chaoyang District, Beijing 100021, China.
Correspondence to: Binghui Shen1 e-mail: bshen@coh.org
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Fen1 mutations result in autoimmunity, chronic inflammation and cancersNature Medicine Article
