Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression.
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. 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. Using gene knockout approaches, we introduced a null mutation into murine Fen1. Mice homozygous for the Fen1 mutation were not obtained, suggesting absence of Fen1 expression leads to embryonic lethality. Most Fen1 heterozygous animals appear normal. However, when combined with a mutation in the adenomatous polyposis coli (Apc) gene, double heterozygous animals have increased numbers of adenocarcinomas and decreased survival. The tumors from these mice show microsatellite instability. Because one copy of the Fen1 gene remained intact in tumors, Fen1 haploinsufficiency appears to lead to rapid progression of cancer.
Department of Medicine and Harvard Partners Center for Genetics and Genomics, Harvard Medical School, Boston, MA 02115, USA. mkucherlapati@harvard.edu
Melanie
M
Kucherlapati
Kan
K
Yang
Mari
M
Kuraguchi
Jie
J
Zhao
Maria
M
Lia
Joerg
J
Heyer
Michael F
MF
Kane
Kunhua
K
Fan
Robert
R
Russell
Anthony M C
AM
Brown
Burkhard
B
Kneitz
Winfried
W
Edelmann
Richard D
RD
Kolodner
Martin
M
Lipkin
Raju
R
Kucherlapati
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D018388:Codon, Terminator / Q000235:genetics; D017931:DNA Primers; D004260:DNA Repair; D004261:DNA Replication; D018450:Disease Progression; D004706:Endodeoxyribonucleases / Q000172:deficiency* / Q000235:genetics*; D045585:Flap Endonucleases; D016368:Frameshift Mutation; D005838:Genotype; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation
D018388:Codon, Terminator; D017931:DNA Primers; D004706:Endodeoxyribonucleases; D045585:Flap Endonucleases