Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression

Melanie Kucherlapati, Kan Yang, Mari Kuraguchi, Jie Zhao, Maria Lia, Joerg Heyer, Michael F. Kane, Kunhua Fan, Robert Russell, Anthony M.C. Brown, Burkhard Kneitz, Winfried Edelmann, Richard D. Kolodner, Martin Lipkin, Raju Kucherlapati

Research output: Contribution to journalArticlepeer-review

199 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9924-9929
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number15
DOIs
StatePublished - Jul 23 2002

ASJC Scopus subject areas

  • General

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