Fen1 mutations result in autoimmunity, chronic inflammation and cancers.
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.
Zheng
Li
L
Department of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute, 1500 East Duarte Road, Duarte, California 91010, USA.
Dai
Huifang
H
Zhou
Mian
M
Li
Mei
M
Singh
Purnima
P
Qiu
Junzhuan
J
Tsark
Walter
W
Huang
Qin
Q
Kernstine
Kemp
K
Zhang
Xuemei
X
Lin
Dongxin
D
Shen
Binghui
B
D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000235:genetics*; D002908:Chronic Disease; D053938:DNA Fragmentation; D004260:DNA Repair; D045585:Flap Endonucleases / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism
D045585:Flap Endonucleases