DNA binding properties of human DNA polymerase η: implications for fidelity and polymerase switching of translesion synthesis

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Abstract
The human XPV (xeroderma pigmentosum variant) gene is responsible for the cancer–prone xeroderma pigmentosum syndrome and encodes DNA polymerase η (pol η), which catalyses efficient translesion synthesis past cis-syn cyclobutane thymine dimers (TT dimers) and other lesions. The fidelity of DNA synthesis by pol η on undamaged templates is extremely low, suggesting that pol η activity must be restricted to damaged sites on DNA. Little is known, however, about how the activity of pol η is targeted and restricted to damaged DNA. Here we show that pol η binds template/primer DNAs regardless of the presence of TT dimers. Rather, enhanced binding to template/primer DNAs containing TT dimers is only observed when the 3′-end of the primer is an adenosine residue situated opposite the lesion. When two nucleotides have been incorporated into the primer beyond the TT dimer position, the pol η-template/primer DNA complex is destabilized, allowing DNA synthesis by DNA polymerases α or δ to resume. Our study provides mechanistic explanations for polymerase switching at TT dimer sites.