Proofreading of DNA polymerase eta-dependent replication errors

Human DNA polymerase eta, the product of the skin cancer susceptibility gen e XPV, bypasses UV photoproducts in template DNA that block synthesis by ot her DNA polymerases. Pol eta lacks an intrinsic proofreading exonuclease an d copies DNA with low fidelity, such that pol eta errors could contribute t o mutagenesis unless they are corrected. Here we provide evidence that pol eta can compete with other human polymerases during replication of duplex D NA, and in so doing it lowers replication fidelity. However, we show that p ol eta has low processivity and extends mismatched primer termini less effi ciently than matched termini, These properties could provide an opportunity for extrinsic exonuclease(s) to proofread pol eta -induced replication err ors. When we tested this hypothesis during replication in human cell extrac ts, pol eta -induced replication infidelity was found to be modulated by ch anging the dNTP concentration and to be enhanced by adding dGMP to a replic ation reaction. Both effects are classical hallmarks of exonucleolytic proo freading. Thus, pol eta is ideally suited for its role in reducing W-induce d mutagenesis and skin cancer risk, in that its relaxed base selectivity ma y facilitate efficient bypass of UV photoproducts, while subsequent proofre ading by extrinsic exonuclease(s) may reduce its mutagenic potential.