Fragile Histidine Triad

Fragile Histidine Triad

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About FHIT / Fragile Histidine Triad:

The fragile histidine triad protein (FHIT) enzyme is encoded by the FHIT gene in humans. It is also known as the human accelerated region and may have played an important role in distinguishing humans from apes.

FHIT Expression
The FHIT protein is a tumor suppressor that is expressed infrequently or not at all in many forms of cancer. FHIT expression is more commonly lost in cancers of people with familial mutations that cause deficiencies in DNA repair genes including BRCA1 and BRCA2 as well as MSH2.

Fragile Histidine Triad Function
In vitro, FHIT acts as a hydrolase, converting adenosine triphosphate (Ap3A) to ADP and AMP. The tumor suppressor signal appears to be the FHIT-Ap3A enzyme-substrate complex. In cancer-derived cells and tumor xenografts, restoring FHIT expression in FHIT-deficient cancer cells triggers apoptosis via the intrinsic caspase pathway.

FHIT Family
FHIT is a member of the broad HIT family of proteins characterized by the histidine triad motif, HxHxHxx, and is comparable to a yeast enzyme, diadenosine tetraphosphate (Ap4A) hydrolase (where x is a hydrophobic residue).

Fragile Histidine Triad Structure
The FHIT gene stretches over 1.6 Mb of genomic DNA and is made up of ten exons.
The FHIT gene encodes a 1.1 kb mRNA that is generated at low levels in the majority of tissues. FHIT includes the common fragile site FRA3B, where carcinogen-induced damage may result in deletions, translocations, and erroneous transcripts. This gene's erroneous transcripts have been detected in about half of all esophageal carcinomas, stomach carcinomas, and other carcinomas. On chromosome 1, there is a pseudogene with sequences that are almost similar to the 5'UTR of FHIT.