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Molecular and Cellular Biology, August 2003, p. 5346-5353, Vol. 23, No. 15
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.15.5346-5353.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Proliferation Failure and Gamma Radiation Sensitivity of Fen1 Null Mutant Mice at the Blastocyst Stage

Elisabeth Larsen, Christine Gran, Barbro Elisabet Sæther, Erling Seeberg, and Arne Klungland*

Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, The National Hospital, University of Oslo, 0027 Oslo, Norway

Received 13 March 2003/ Returned for modification 10 April 2003/ Accepted 8 May 2003

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.

* Corresponding author. Mailing address: Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, The National Hospital, University of Oslo, 0027 Oslo, Norway. Phone: 47-23074069. Fax: 47-23074061. E-mail: aklungla{at}labmed.uio.no.

Molecular and Cellular Biology, August 2003, p. 5346-5353, Vol. 23, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.15.5346-5353.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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