Fig. 6
From: Linear mitochondrial DNA is rapidly degraded by components of the replication machinery
Models of double-strand degradation of mtDNA and its role in generation of rearrangements. a POLG, TWNK, and MGME1 play a role in both replication (upper half of the panel) and degradation (lower half of the panel) of mitochondrial DNA. Upon replication, the net movement of the complex (indicated by the large shaded arrow) corresponds to the polymerase activity of POLG. Under these conditions, MGME1 can remove flap structures, thus creating ligatable ends9. During degradation, net movement is reversed and corresponds to the exonuclease activity of POLG. b Proposed role of linear mtDNA degradation in generation of rearrangements. Since double-strand breaks (DBS) are efficiently removed in normal tissues (blue), most somatic mtDNA deletions are generated by replication slippage25, and thus are typically associated with direct repeats (black boxes) around the breakpoints (‘I’, class I type of mtDNA deletions, Table 1). Repair by homologous recombination (HR) or microhomology-mediated end joining (MMEJ) is not an efficient pathway in animal mitochondria34. In the case of replication machinery dysfunction (red), frequent replication stalling leads to increased generation of double-strand breaks (DSB). Additionally, the breakdown of linear mtDNA is inhibited. The persistence of linear mtDNA favors the formation of class II deletions (‘II’) by ligase-III-dependent non-homologous end joining (NHEJ). Supporting this hypothesis, an increased frequency of class II mtDNA deletions (not being associated with direct repeats) is observed in patients carrying pathogenic mutations in MGME1, TWNK, and POLG (Table 1)
