Characterization of the role of Fhit in suppression of DNA damage

Joshua C. Saldivar, Jessica Bene, Seyed Ali Hosseini, Satoshi Miuma, Susan Horton, Nyla A. Heerema, Kay Huebner

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

The fragile histidine triad protein, Fhit, has a number of reported tumor suppressive functions which include signaling of apoptosis in cancer cells in vitro and in vivo, modulation of the DNA damage response, down-regulation of target oncogene expression, suppression of tumor growth in vivo, and suppression of cancer cell invasion and metastasis. Most of these functions of Fhit have been observed on exogenous re-expression of Fhit in Fhit-negative cancer cells. However, little is known about the tumorigenic changes that occur in normal or precancerous cells following loss of Fhit expression. Recently, we have shown that shortly after loss of Fhit expression, cells exhibit signs of DNA replication stress-induced DNA damage and develop genomic instability. Here, we extend these findings through investigation of different factors that affect Fhit function to prevent DNA damage. We found that Fhit activity is dependent upon a functional HIT domain and the tyrosine-114 residue, previously shown to be required for tumor suppression by Fhit. Furthermore, Fhit function was shown to be independent of exogenous and endogenous sources of oxidative stress. Finally, Fhit function was shown to be dependent upon Chk1 kinase activity, but independent of Atr or Atm kinases. Evidence suggests that Fhit and Chk1 kinase cooperate to prevent replication stress-induced DNA damage. These findings provide important and unexpected insights into the mechanism whereby loss of Fhit expression contributes to cell transformation.

Original languageEnglish (US)
Pages (from-to)77-85
Number of pages9
JournalAdvances in Biological Regulation
Volume53
Issue number1
DOIs
StatePublished - Jan 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'Characterization of the role of Fhit in suppression of DNA damage'. Together they form a unique fingerprint.

Cite this