Helping the hypermutator: The Fhit-APOBEC connection

Abstract

The APOBEC3B (A3B) somatic mutation signature (C>T point mutations at TC dinucleotides) is widespread in human cancers, but stratification of tumors based on A3B gene expression shows weak positive correlation with hypermutation. Further stratification with factors that increase the availability of ssDNA, the preferred substrate for A3B, will likely enhance this correlation and increase our understanding of the mechanisms behind this most pervasive mutational signature in human cancers. Alterations at the FHIT gene locus occur early in cancer initiation, leading to reduction or complete loss of Fhit protein expression in over 50% of cancers. Fhit loss causes replication stress and genome instability in cells without cell cycle arrest or apoptosis, allowing cells to accumulate DNA damage with each subsequent cell division. Thus, Fhit negative cells harbor increased availability of A3B target ssDNA, leading to our proposal that Fhit loss creates optimal A3B substrates that facilitate A3B-mediated mutagenesis. This research highlight summarizes our recent findings concerning the cooperation of Fhit loss-induced DNA damage and A3B overexpression. Briefly, DNA from FHIT deficient lung adenocarcinomas that also show high A3B expression exhibit the highest frequency of total mutations and A3B signature point mutations. In vitro , these mutations could be rescued by inhibiting the replication stress caused by Fhit loss. We also consider the role of Fhit loss itself in mutagenesis and what other enzymes may exploit Fhit loss-induced genome instability to increase mutagenesis. The recent advances in our understanding of A3B and Fhit loss-induced mutagenesis are applicable to the most common types of human cancers and involve events that occur at the very onset of cancer initiation.