浙江大学分子生物学课件_附件.pdf

A R T I C L E S e Fen1 mutations result in autoimmunity, chronic n i c i d inflammation and cancers e m e r u 1 1 1 1 1 1 2 3 t Li Zheng , Huifang Dai , Mian Zhou , Mei Li , Purnima Singh , Junzhuan Qiu , Walter Tsark , Qin Huang , a n 4 5 5 1 / Kemp Kernstine , Xuemei Zhang , Dongxin Lin Binghui Shen m o c . e r Functional deficiency of the FEN1 gene has been suggested to cause genomic instability and cancer predisposition. We have u t a identified a group of FEN1 mutations in human cancer specimens. Most of these mutations abrogated two of three nuclease n . w activities of flap endonuclease 1 (FEN1). To demonstrate the etiological significance of these somatic mutations, we inbred a w w 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 p t t mutant mice were predisposed to autoimmunity, chronic inflammation and cancers. The mutator phenotype results in the initiation h p of cancer, whereas chronic inflammation promotes the cancer progression. The current work exemplifies the approach of studying u o the mechanisms of individual polymorphisms and somatic mutations in cancer development, and may serve as a reference in r G developing new therapeutic regimens through the suppression of inflammatory responses. g n i h s i l Cancer arises from the accumulation of mutations in structural and background results in microsatellite instability and promotes cancer b u functional elements of the gen