Single-nucleotide polymorphism of the DNA cytosine deaminase APOBEC3H haplotype I leads to enzyme destabilization and correlates with lung cancer.

A number of APOBEC family DNA cytosine deaminases can induce mutations in tumor cells. APOBEC3H haplotype I is one of the deaminases that has been proposed to cause mutations in lung cancer. Here, we confirmed that APOBEC3H haplotype I can cause uracil-induced DNA damage in lung cancer cells that results in γH2AX foci. Interestingly, the database of cancer biomarkers in DNA repair genes (DNArCdb) identified a single-nucleotide polymorphism (rs139298) of APOBEC3H haplotype I that is involved in lung cancer. While we thought this may increase the activity of APOBEC3H haplotype I, instead we found through computational modeling and cell-based experiments that this single-nucleotide polymorphism causes the destabilization of APOBEC3H Haplotype I. Computational analysis suggests that the resulting K121E change affects the structure of APOBEC3H leading to active site disruption and destabilization of the RNA-mediated dimer interface. A K117E mutation in a K121E background stabilized the APOBEC3H haplotype I, thus enabling biochemical study. Subsequent analysis showed that K121E affected catalytic activity, single-stranded DNA binding and oligomerization on single-stranded DNA. The destabilization of a DNA mutator associated with lung cancer supports the model that too much APOBEC3-induced mutation could result in immune recognition or death of tumor cells.