Chemical-induced cancer incidence and underlying mechanisms in Fen1 mutant mice.
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.
Key Laboratory of Chinese Ministry of Agriculture for Nuclear-Agricultural Sciences, Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou, China.
H
H
Xu
L
L
Zheng
H
H
Dai
M
M
Zhou
Y
Y
Hua
B
B
Shen
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002460:Cell Line; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication; D004195:Disease Models, Animal; D045585:Flap Endonucleases / Q000235:genetics* / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006861:Hydrogen Peroxide / Q000633:toxicity; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D017354:Point Mutation
D008770:Methylnitrosourea; D006861:Hydrogen Peroxide; D045585:Flap Endonucleases