The March 2017 Editor's Choice article is "Tumor-Associated APE1 Variant Exhibits Reduced Complementation Efficiency, But Does Not Promote Cancer Cell Phenotypes" by Jennifer Illuzi, Daniel McNeill, Paul Bastian, Boris Brenerman, Robert Wersto, Helen Russell, Fred Bunz, Peter McKinnon, Kevin Becker and David Wilson.
In the March 2017 issue of Environmental and Molecular Mutagenesis Jennifer Illuzzi, David Wilson and their co-investigators at the National Institute on Aging, Johns Hopkins University and St. Jude Children’s Research Hospital report on the importance of the base excision repair protein APE1 in mammalian cell biology. They studied the effects of exogenous expression of wildtype human APE1 protein or the tumor-associated somatic variant APE1-R237C in mouse cells and reduced expression of APE1 protein in human cells. Their results demonstrate that the R237C variant protein poorly substitutes for wildtype APE1 in preserving essential growth functions in mouse cells, and displays reduced ability relative to wildtype in preserving viability when cells are challenged with toxic concentrations of a DNA methylating agent, methyl methane sulfonate. However, the cancer-associated somatic variant did not transform mouse cells when over-expressed, suggesting that it may function as a susceptibility allele that renders cells more sensitive to DNA damage due to reduced DNA repair activity. Genetic deletion of one APE1 allele in a human colon cancer cell line reduced expression of APE1 protein by about 50% and sensitized cells to base damage in DNA. Short-term cell survival of partially deleted cells was normal, but long-term survival was severely reduced. Analysis of global gene expression in the long-term survivors revealed alterations in gene expression affecting many cellular organelles, not just the nucleus. The profound reprogramming of gene expression in long-term survivors demonstrates the amplification of cellular pathology that results from a modest reduction in the expression of an essential gene. This report exemplifies the importance of the base excision repair protein APE1 in the preservation of cellular homeostasis and genomic integrity. Environ. Mol. Mutagen. 58:84-98, 2017. © 2017 Wiley Periodicals, Inc.