Since DNA polymerase g is sensitive to oxidative modiÞcation this has the potential to inactivate or alter polymerase g expression. An elegant study by Graziewicz et al. demonstrated that polymerase g is a major target for ROS and that this oxidation can inactivate the catalytic subunit responsible for gap Þlling activity during DNA repair [90]. In addition, it is now known that polymerase g is the rate-limiting step in the BER, and inactivation of this protein is likely to increase the buildup of cytotoxic BER pathway intermediates which include single strand breaks [95].

10.4.6Other Mitochondrial DNA Repair Pathways

10.4.6.1Double-Strand Break Repair (DSBR)

Double strand breaks can be repaired by homologous recombination (HR) or nonhomologous end joining (NHEJ). Both mechanisms are thought to be present in mammalian mitochondria [122, 123] and recent studies suggest both homology-dependent recombination and homology-independent repair occur [124, 125], though recombinant molecules may also arise from strand exchange during DNA replication. Rad51C, a recA homologue, and Xrcc3, also involved in homologous recombination in the nucleus, have recently been shown to localize to mitochondria and interact with mtDNA. The levels of these proteins in the organelle increase with oxidative stress while their depletion causes a decrease in mtDNA copy number [126].

10.4.6.2Mismatch Repair (MMR)

DNA repair pathways that are active against mismatch bases have been recently reported in mitochondria [127]. Nuclear mismatch repair (MMR) factors have not been detected in mitochondria; however, it has been shown that mitochondrial DNA and nuclear DNA have distinct MMR pathways [127, 128]. The Y box binding protein (YB-1) seems to have a signiÞcant role in mitochondrial MMR [127], which is intriguing, as YB-1 has previously been shown to be a key component in nuclear BER [129]. DNA mismatches are not a direct consequence of oxidative stress to mitochondria, but they may increase because of oxidative damage to polymerase g.

10.4.6.3Translesion Synthesis (TLS) and Damage Tolerance

Part of the tolerance to DNA damage lies in the ability of cells to replicate across damaged DNA, via a process called translesion synthesis (TLS) [130]. TLS is the process by which a DNA lesion is bypassed by the incorporation of a nucleotide opposite to the lesion. Without DNA damage tolerance, cells face the risk of replication fork collapse, translocations, chromosome aberrations, and cell death [131, 132]. The presence of TLS in mitochondria is still open to discussion. However, support