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The FHIT gene product: tumor suppressor and genome “caretaker”

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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.

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  1. Joshua C. Saldivar

    Present address: Department of Chemical and Systems Biology, Stanford University School of Medicine, 318 Campus Drive, Clark Center W350, Stanford, CA, 94305, USA

  2. Seyed Ali Hosseini

    Present address: John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, 1501 NW 10th Ave., BRB 425 Miami, Miami, FL, 33136, USA

Authors and Affiliations

  1. Biomedical Sciences Graduate Program, Ohio State University Wexner Medical Center, Columbus, OH, USA

    Catherine E. Waters

  2. Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Biomedical Research Tower, Rm 916, 460 W. 12th Ave, Columbus, OH, 43210, USA

    Catherine E. Waters & Kay Huebner

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Waters, C.E., Saldivar, J.C., Hosseini, S.A. et al. The FHIT gene product: tumor suppressor and genome “caretaker”. Cell. Mol. Life Sci. 71, 4577–4587 (2014). https://doi.org/10.1007/s00018-014-1722-0

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