Related Experiment Video
Updated: Jul 4, 2026
Functional Manipulation of Maternal Gene Products Using In Vitro Oocyte Maturation in Zebrafish
Published on: April 22, 2017
Early-onset lymphoma and extensive embryonic apoptosis in two domain-specific Fen1 mice mutants
Elisabeth Larsen1, Liv Kleppa, Trine J Meza
1Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet Medical Center and University of Oslo, USA.
Abstract:
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.
Insights
Flap endonuclease 1 (FEN1) mutations impact DNA replication and repair. The nuclease-active site mutation causes B-cell lymphomas in mice, while PCNA-binding domain disruption leads to embryonic lethality.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Flap endonuclease 1 (FEN1) is crucial for Okazaki fragment processing during DNA replication and participates in DNA repair pathways.
- FEN1's interaction with proliferating cell nuclear antigen (PCNA) is essential for its function in DNA metabolism.
Purpose of the Study:
- To investigate the in vivo roles of FEN1's nuclease activity and PCNA interaction domain.
- To generate and characterize novel mouse models with specific FEN1 mutations.
Main Methods:
- Gene targeting in mice to create point mutations in FEN1's active site (Fen1(E160D/E160D)) and PCNA interaction domain (Fen1(DeltaPCNA/DeltaPCNA)).
- Phenotypic analysis of mutant mice, including tumor incidence and embryonic development.
Main Results:
- Fen1(E160D/E160D) mice exhibit a high incidence of B-cell lymphomas, particularly in females, with over 90% developing tumors by 16 months.
- Fen1(DeltaPCNA/DeltaPCNA) mouse embryos display severe apoptosis in the forebrain and vertebrae, resulting in embryonic lethality between E9.5 and E11.5.
Conclusions:
- FEN1's nuclease activity is critical for preventing lymphomagenesis.
- The PCNA interaction domain of FEN1 is essential for embryonic development, highlighting its vital role in DNA replication and repair fidelity.
