Disease relevance of Fen1

• Disruption of the FEN-1/PCNA Interaction Results in DNA Replication Defects, Pulmonary Hypoplasia, Pancytopenia, and Newborn Lethality in Mice [1].

High impact information on Fen1

• Flap endonuclease (Fen1) is required for DNA replication and repair, and defects in the gene encoding Fen1 cause increased accumulation of mutations and genome rearrangements [2].
• Because mutations in some genes involved in these processes cause cancer predisposition, we investigated the possibility that Fen1 may function in tumorigenesis of the gastrointestinal tract [2].
• Collectively, our data demonstrate the importance of the FEN-1/PCNA complex in DNA replication and in the embryonic development of mice [1].
• Proliferation failure and gamma radiation sensitivity of Fen1 null mutant mice at the blastocyst stage [3].
• 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 [3].

Biological context of Fen1

• The mouse Fen1 gene, which has two exons, is located immediately adjacent to the gene corresponding to full-length cDNA of Riken 1810006K21 (1810006K21Rik) in a head-to-head orientation [4].
• Increased Fen1 levels upon UV-C exposure are due to transcriptional activation, as revealed by inhibitor studies [5].
• 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 [3].
• 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 [3].
• Heterozygote animals appear normal, whereas complete depletion of FEN1 causes early embryonic lethality [3].

Anatomical context of Fen1

• Transgenic expression of Fen1 in p53 null cells attenuated UV-C light-induced DNA replication inhibition, supporting the hypothesis that Fen1 induction is involved in the recovery of cells from DNA damage [5].
• The mouse Fen-1 gene is assigned to chromosome 19 based on somatic cell hybrids [6].

Associations of Fen1 with chemical compounds

• Divalent metal ions, Mg(2+) or Mn(2+), are required for the active center of FEN-1 nucleases [7].

Regulatory relationships of Fen1

• Fen1 is induced p53 dependently and involved in the recovery from UV-light-induced replication inhibition [5].

Other interactions of Fen1

• These results suggested the association of an end-processing activity (exonuclease/helicase + flap endonuclease) along with the end-joining ligase(s) [8].

Analytical, diagnostic and therapeutic context of Fen1

• 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 [3].

References