Human DNA polymerase lambda is a proficient extender of primer ends paired to 7,8-dihydro-8-oxoguanine

Pol λ is a DNA repair enzyme with a high affinity for dNTPs, an intrinsic dRP lyase activity, a BRCT domain involved in interactions with NHEJ factors, and also capable to interact with the PCNA processivity factor. Based on this potential, Pol λ could play a role in BER, V(D)J recombination, NHEJ and TLS.Here we show that human Pol λ uses a templating 7,8-dihydro-8-oxoguanine (8oxoG) base, a common mutagenic form of oxidative damage, as efficiently as an undamaged dG, but giving rise to the alternative insertion of either dAMP or dCMP. However, Pol λ strongly discriminated against the extension of the mutagenic 8oxoG:dAMP pair. Conversely, Pol λ readily extended the non-mutagenic 8oxoG:dCMP pair with an efficiency that was even higher than that displayed on undamaged dG:dCMP pair. A similar capacity for non-mutagenic extension was also shown to occur in the case of O6-methylguanine (m6G), a mutagenic and cytotoxic DNA adduct. A comparison of these novel properties of human Pol λ with those of other DNA polymerases involved in TLS will be discussed. Interestingly, when double-strand breaks are associated to base damage, modifications as 8oxoG could be eventually part of the synapsis required to join ends, and therefore, the capacity of Pol λ either to insert opposite 8oxoG or to extend correct base pairs containing such a damage could be beneficial for its role in NHEJ.