yG807, equivalent to hG1051, is part of a partitioning loop that modulates the partitioning of the primer strand between the polymerase and the exonuclease active sites by forming stable contacts with correctly base-paired primer-template DNA and destabilizing primertemplate DNA that contains mispairs This subdomain is adjacent to the orienter module, whose role is to position correctly the partitioning loop. Mutations in the orienter loop and in the partitioning loop both result in reduced DNA-binding affinity, reduced polymerase activity, increased point mutability and increased extended mutability. yA692T, equivalent to hA889, is part of a b-sheet which surrounds the catalytic residues in the palm. Mutations in this b-sheet are predicted to reduce polymerase activity, and this effect was observed for A692T mutation in yeast. yR467,LDK378equivalent to hR574, is part of a subdomain responsible for the intrinsic processivity of Pol gamma. As a matter of fact, mutation yR467W results in a decreased processivity. We showed that these recessive mutations with reduced polymerase activity or processivity are insensitive to antioxidants treatment. Thus, we speculate that different Pol gamma mutations exert their negative effect according to two distinct ways. The first one, rescued by the treatment with antioxidants, can be related to the increased incorporation of 8-oxo-dG: in presence of antioxidant molecules the concentration of oxidized nucleotides and, as a consequence, their incorporation in the mtDNA is reduced. The inability of Pol zeta to rescue these Mip1 mutations may depend partially on the low efficiency of Pol zeta to LDN-193189 1062368-24-4incorporate nucleosides opposite to 8-oxo-dG. The second way, rescued by Rev3 overexpression, could be related to reduced polymerase activity, processivity and/or TLS synthesis of mutated mtDNA polymerase as in the case of C261R, R467W, A692T and G807R mutations. Two modes of action may account for ability of Rev3 to rescue this kind of mip1 mutations. i) Pol zeta could participate directly to the replication of undamaged mtDNA at the replicative fork partially playing the role of Mip1, as it was recently demonstrated in the case of defective nuclear replisome due to mutations in the replicative polymerases. Interestingly, the rescue is observed for mutations which cause reduced DNA binding affinity or for which reduced DNA binding affinity is predicted. ii) Alternately, Pol zeta could partially substitute mutant Mip1 defective of TLS, either during the incorporation opposite to a lesion or the extension from mismatched terminally nucleotides. Reports of translesion synthesis by Pol gamma are limited. In vitro studies showed that Pol gamma from higher eukaryotes is an enzyme with a low TLS activity: it can bypass 8-oxo-dG incorporating dCMP or dAMP, but stalls the majority of the time opposite abasic sites and opposite adducts containing benzo pyrene and benzo phenantrene.