Early-onset lymphoma and extensive embryonic apoptosis in two domain-specific Fen1 mice mutants.
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(DeltaPCNA/DeltaPCNA)). 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(DeltaPCNA/DeltaPCNA) mouse embryos show extensive apoptosis in the forebrain and vertebrae area and die around stage E9.5 to E11.5.
Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet Medical Center and University of Oslo, USA.
Elisabeth
E
Larsen
Liv
L
Kleppa
Trine J
TJ
Meza
Leonardo A
LA
Meza-Zepeda
Christina
C
Rada
Cesilie G
CG
Castellanos
Guro F
GF
Lien
Gaute J
GJ
Nesse
Michael S
MS
Neuberger
Jon K
JK
Laerdahl
Richard
R
William Doughty
Arne
A
Klungland
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004260:DNA Repair; D004261:DNA Replication; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D045585:Flap Endonucleases / Q000502:physiology*; D005803:Genes, Immunoglobulin / Q000235:genetics; D005804:Genes, Lethal; D007333:Insulin Resistance; D008223:Lymphoma / Q000209:etiology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D009693:Nucleic Acid Hybridization; D009765:Obesity / Q000209:etiology; D018809:Proliferating Cell Nuclear Antigen / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic
D016895:Culture Media, Serum-Free; D018809:Proliferating Cell Nuclear Antigen; D045585:Flap Endonucleases