Abstract
Deletions in mitochondrial DNA (mtDNA) are associated with diverse human pathologies including cancer, aging and mitochondrial disorders. Large-scale deletions span kilobases in length and the loss of these associated genes contributes to crippled oxidative phosphorylation and overall decline in mitochondrial fitness. There is not a united view for how mtDNA deletions are generated and the molecular mechanisms underlying this process are poorly understood. This review discusses the role of replication and repair in mtDNA deletion formation as well as nucleic acid motifs such as repeats, secondary structures, and DNA damage associated with deletion formation in the mitochondrial genome. We propose that while erroneous replication and repair can separately contribute to deletion formation, crosstalk between these pathways is also involved in generating deletions.
Highlights
Mitochondria are descendants of ␣-proteobacteria and are responsible for energy production in most eukaryotic cells
The fact that mitochondrial DNA (mtDNA) molecules harboring double-stranded breaks (DSBs) in mammalian cells are rapidly degraded by a mechanism involving the replication proteins Pol␥, Twinkle, and MGME1 [72,73] indicates that mtDNA DSBs are handled differently than the repair-oriented mechanisms acting in the nucleus
Deletions in mtDNA ablate key genes that contributes to perturbed mitochondrial bioenergetics observed in several human diseases and mitochondrial disorders
Summary
Mitochondria are descendants of ␣-proteobacteria and are responsible for energy production in most eukaryotic cells. This review discusses the role of replication and repair in mtDNA deletion formation as well as nucleic acid motifs such as repeats, secondary structures, and DNA damage associated with deletion formation in the mitochondrial genome. We discuss salient mutations in the mitochondrial replisomal proteins DNA Pol␥ , Twinkle and MGME1, encoded by the POLG1, TWNK and MGME1 genes, respectively, that are associated with several human diseases and the accumulation of mtDNA deletions.
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