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Early-Onset Lymphoma and Extensive Embryonic Apoptosis in Two Domain-Specific Fen1 Mice Mutants

¹ Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet Medical Center and University of Oslo; ² Norwegian Microarray Consortium, Department for Molecular Biosciences, Faculty of Mathematics and Natural Sciences, and ³ Department of Molecular Biosciences, University of Oslo; ⁴ Department of Tumor Biology, Institute for Cancer Research, Radiumhospitalet, Rikshospitalet Medical Center; ⁵ Department of Safety, PCS Biology, GE Healthcare Bio-sciences, Oslo, Norway; and ⁶ Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom

Requests for reprints: Arne Klungland, Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet HF and University of Oslo, Sognvannsveien 20, Oslo 0027, Norway. Phone: 47-2307-4072; Fax: 47-2307-4061; E-mail: aklungla{at}medisin.uio.no.

Key Words: DNA repair • FEN1 • Lymphoma

Flap endonuclease 1 (FEN1) processes Okazaki fragments in lagging strand DNA synthesis, and FEN1 is involved in several DNA repair pathways. The interaction of FEN1 with the proliferating cell nuclear antigen (PCNA) processivity factor is central to the function of FEN1 in both DNA replication and repair. Here we present two gene-targeted mice with mutations in FEN1. The first mutant mouse carries a single amino acid point mutation in the active site of the nuclease domain of FEN1 (Fen1^E160D/E160D), and the second mutant mouse contains two amino acid substitutions in the highly conserved PCNA interaction domain of FEN1 (Fen1^PCNA/PCNA). Fen1^E160D/E160D mice develop a considerably elevated incidence of B-cell lymphomas beginning at 6 months of age, particularly in females. By 16 months of age, more than 90% of the Fen1^E160D/E160D females have tumors, primarily lymphomas. By contrast, Fen1^PCNA/PCNA mouse embryos show extensive apoptosis in the forebrain and vertebrae area and die around stage E9.5 to E11.5. [Cancer Res 2008;68(12):4571–8]