Proliferation failure and gamma radiation sensitivity of Fen1 null mutant mice at the blastocyst stage.
Flap endonuclease 1 (FEN1) has been shown to remove 5' overhanging flap intermediates during base excision repair and to process the 5' ends of Okazaki fragments during lagging-strand DNA replication in vitro. To assess the in vivo role of the mammalian enzyme in repair and replication, we used a gene-targeting approach to generate mice lacking a functional Fen1 gene. Heterozygote animals appear normal, whereas complete depletion of FEN1 causes early embryonic lethality. Fen1(-/-) blastocysts fail to form inner cell mass during cellular outgrowth, and a complete inactivation of DNA synthesis in giant cells of blastocyst outgrowth was observed. Exposure of Fen1(-/-) blastocysts to gamma radiation caused extensive apoptosis, implying an essential role for FEN1 in the repair of radiation-induced DNA damage in vivo. Our data thus provide in vivo evidence for an essential function of FEN1 in DNA repair, as well as in DNA replication.
Larsen
Elisabeth
E
Centre for Molecular Biology and Neuroscience, Institute of Medical Microbiology, The National Hospital, University of Oslo, 0027 Oslo, Norway.
Gran
Christine
C
Saether
Barbro Elisabet
BE
Seeberg
Erling
E
Klungland
Arne
A
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D001755:Blastocyst / Q000378:metabolism; D002455:Cell Division; D004260:DNA Repair; D004261:DNA Replication; D004706:Endodeoxyribonucleases / Q000235:genetics* / Q000502:physiology*; D045585:Flap Endonucleases; D005720:Gamma Rays; D005822:Genetic Vectors; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009154:Mutation; D018384:Oxidative Stress; D020161:Physical Chromosome Mapping; D016133:Polymerase Chain Reaction; D013997:Time Factors
D004706:Endodeoxyribonucleases; D045585:Flap Endonucleases