The FHIT gene product: Tumor suppressor and genome "caretaker"

Catherine E. Waters, Joshua C. Saldivar, Seyed Ali Hosseini, Kay Huebner

Research output: Contribution to journalReview articlepeer-review

50 Scopus citations

Abstract

The FHIT gene at FRA3B is one of the earliest and most frequently altered genes in the majority of human cancers. It was recently discovered that the FHIT gene is not the most fragile locus in epithelial cells, the cell of origin for most Fhit-negative cancers, eroding support for past claims that deletions at this locus are simply passenger events that are carried along in expanding cancer clones, due to extreme vulnerability to DNA damage rather than to loss of FHIT function. Indeed, recent reports have reconfirmed FHIT as a tumor suppressor gene with roles in apoptosis and prevention of the epithelial-mesenchymal transition. Other recent works have identified a novel role for the FHIT gene product, Fhit, as a genome "caretaker." Loss of this caretaker function leads to nucleotide imbalance, spontaneous replication stress, and DNA breaks. Because Fhit loss-induced DNA damage is "checkpoint blind," cells accumulate further DNA damage during subsequent cell cycles, accruing global genome instability that could facilitate oncogenic mutation acquisition and expedite clonal expansion. Loss of Fhit activity therefore induces a mutator phenotype. Evidence for FHIT as a mutator gene is discussed in light of these recent investigations of Fhit loss and subsequent genome instability.

Original languageEnglish (US)
Pages (from-to)4577-4587
Number of pages11
JournalCellular and Molecular Life Sciences
Volume71
Issue number23
DOIs
StatePublished - Oct 5 2014
Externally publishedYes

Keywords

  • Common fragile sites
  • FRA3B/FHIT
  • Genome instability
  • Mutator phenotype
  • Replication stress

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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