Replicative Stress and the FHIT Gene: Roles in Tumor Suppression, Genome Stability and Prevention of Carcinogenesis.

Jenna Karras,Carolyn Paisie,Kay Huebner

doi:10.3390/cancers6021208

Abstract

The fragile FHIT gene, encompassing the chromosomal fragile site FRA3B, is an early target of DNA damage in precancerous cells. While vulnerable to DNA damage itself, FHIT protein expression is essential to protect from DNA damage-induced cancer initiation and progression by modulating genome stability, oxidative stress and levels of accumulating DNA damage. Thus, FHIT, whose expression is lost or reduced in many human cancers, is a tumor suppressor and genome caretaker whose loss initiates genome instability in preneoplastic lesions. Ongoing studies are seeking more detailed understanding of the role of FHIT in the cellular response to oxidative damage. This review discusses the relationship between FHIT, reactive oxygen species production, and DNA damage in the context of cancer initiation and progression.

Highlights

Genomic instability is a hallmark of human neoplasia, present in varying degrees in all stages of cancer, from precancerous to advanced cancer
While the FRA3B locus is highly vulnerable to DNA damage due to replication stress, the FHIT protein, paradoxically, is a tumor suppressor and genome caretaker that modulates genome stability, oxidative stress and level of DNA damage that accumulates beginning in precancerous lesions [5,6,7,8,9,10,11,12]
Protein, paradoxically, is a tumor suppressor and genome caretaker that modulates genome stability, oxidative stress and level of DNA damage that accumulates beginning in precancerous lesions

Summary

Introduction

Genomic instability is a hallmark of human neoplasia, present in varying degrees in all stages of cancer, from precancerous to advanced cancer. DNA replication, aberrant checkpoint responses, and oxidative stress contribute to the expansion of instability throughout the genome during neoplastic progression. The FHIT gene is positioned at one of the most active CFSs, FRA3B, and is one of the most frequently altered genes in preneoplasia and cancer [3]. Alterations at this locus include deletions, translocations and promoter methylation, often resulting in the loss or reduction of expression of the FHIT protein. The instability at FRA3B and the subsequent loss of FHIT protein expression is detected in precancerous cells and precedes the instability observed at other genomic loci. We will discuss the ability of the FHIT protein to participate in the response to oxidative damage, and the implications for neoplastic progression

Oxidative Stress and the Mitochondrial Fraction of FHIT Protein

The FHIT-Substrate Complex

FHIT and Genome Stability

Discussion

Conclusions