Incorporation of inosine into DNA by human polymerase eta (Polη): kinetics of nucleotide misincorporation and structural basis for the mutagenicity

Inosine, a purine nucleoside containing the hypoxanthine (HX) nucleobase, can form in DNA via hydrolytic deamination of adenine. Due to its structural similarity to guanine and the geometry of Watson-Crick base pairs, inosine can mispair with cytosine upon cataly-sis by DNA polymerases, leading to AT-* GC mutations. Additionally, inosine plays an essential role in purine nucleotide biosynthesis, and inosine triphosphate is present in living cells. In a recent publication, Averill and Jung examined the possibility of polri cata-lyzed incorporation of deoxyinosine triphosphate (dITP) across dC and dT in a DNA tem-plate. They found that dITP can be incorporated across C or T, with the ratio of 13.7. X ray crystallography studies revealed that the mutagenic incorporation of dITP by human polri was affected by several factors including base pair geometry in the active site of the polymerase, tautomerization of nucleobases, and the interaction of the incoming dITP nucleotide with active site residues of polri. This study demonstrates that TLS incorpor-ation of inosine monophosphate (IMP) into growing DNA chains contributes to its muta-genic potential in cells.