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Pfeiffer, Annika
Publications (2 of 2) Show all publications
Forslund, J. M. E., Pfeiffer, A., Stojkovič, G., Wanrooij, P. H. & Wanrooij, S. (2018). The presence of rNTPs decreases the speed of mitochondrial DNA replication. PLoS Genetics, 14(3), Article ID e1007315.
Open this publication in new window or tab >>The presence of rNTPs decreases the speed of mitochondrial DNA replication
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2018 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 3, article id e1007315Article in journal (Refereed) Published
Abstract [en]

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 mitochondnal 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 rntDNA depletion syndrome (MDS) that are associated with imbalanced cellular dNTP pools. Our results show that at the rNTPidNIP ratios that are expected to prevail in such disease states, Pol gamma enters a polymerasetexonuclease 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.

Place, publisher, year, edition, pages
Public library science, 2018
National Category
Medical Genetics
urn:nbn:se:umu:diva-146802 (URN)10.1371/journal.pgen.1007315 (DOI)000428840600053 ()29601571 (PubMedID)
Available from: 2018-04-26 Created: 2018-04-26 Last updated: 2018-06-09Bibliographically approved
Torregrosa-Muñumer, R., Forslund, J. M. E., Goffart, S., Pfeiffer, A., Stojkovič, G., Carvalho, G., . . . Pohjoismäki, J. L. O. (2017). PrimPol is required for replication reinitiation after mtDNA damage. Proceedings of the National Academy of Sciences of the United States of America, 114(43), 11398-11403
Open this publication in new window or tab >>PrimPol is required for replication reinitiation after mtDNA damage
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2017 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 43, p. 11398-11403Article in journal (Refereed) Published
Abstract [en]

Eukaryotic PrimPol is a recently discovered DNA-dependent DNA primase and translesion synthesis DNA polymerase found in the nucleus and mitochondria. Although PrimPol has been shown to be required for repriming of stalled replication forks in the nucleus, its role in mitochondria has remained unresolved. Here we demonstrate in vivo and in vitro that PrimPol can reinitiate stalled mtDNA replication and can prime mtDNA replication from nonconventional origins. Our results not only help in the understanding of how mitochondria cope with replicative stress but can also explain some controversial features of the lagging-strand replication.

Place, publisher, year, edition, pages
National Academy of Sciences, 2017
DNA repair, fork rescue, mtDNA damage, mtDNA replication
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
urn:nbn:se:umu:diva-141811 (URN)10.1073/pnas.1705367114 (DOI)000413520700056 ()29073063 (PubMedID)
Available from: 2017-11-27 Created: 2017-11-27 Last updated: 2018-06-09Bibliographically approved

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