| First Author | Forslund JME | Year | 2018 |
| Journal | PLoS Genet | Volume | 14 |
| Issue | 3 | Pages | e1007315 |
| PubMed ID | 29601571 | Mgi Jnum | J:261916 |
| Mgi Id | MGI:6154781 | Doi | 10.1371/journal.pgen.1007315 |
| Citation | Forslund JME, et al. (2018) The presence of rNTPs decreases the speed of mitochondrial DNA replication. PLoS Genet 14(3):e1007315 |
| abstractText | Ribonucleotides (rNMPs) are frequently incorporated during replication or repair by DNA polymerases and failure to remove them leads to instability of nuclear DNA (nDNA). Conversely, rNMPs appear to be relatively well-tolerated in mitochondrial DNA (mtDNA), although the mechanisms behind the tolerance remain unclear. We here show that the human mitochondrial DNA polymerase gamma (Pol gamma) bypasses single rNMPs with an unprecedentedly high fidelity and efficiency. In addition, Pol gamma exhibits a strikingly low frequency of rNMP incorporation, a property, which we find is independent of its exonuclease activity. However, the physiological levels of free rNTPs partially inhibit DNA synthesis by Pol gamma and render the polymerase more sensitive to imbalanced dNTP pools. The characteristics of Pol gamma reported here could have implications for forms of mtDNA depletion syndrome (MDS) that are associated with imbalanced cellular dNTP pools. Our results show that at the rNTP/dNTP ratios that are expected to prevail in such disease states, Pol gamma enters a polymerase/exonuclease idling mode that leads to mtDNA replication stalling. This could ultimately lead to mtDNA depletion and, consequently, to mitochondrial disease phenotypes such as those observed in MDS. |
