Mitochondrial genetic variation is enriched in G-quadruplex regions that stall DNA synthesis in vitro
| العنوان: | Mitochondrial genetic variation is enriched in G-quadruplex regions that stall DNA synthesis in vitro |
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| المؤلفون: | Luigi Ferrucci, Katrina N Estep, Thomas J. Butler, Robert W. Maul, David Schlessinger, Andrew R. Wood, Marcus A. Tuke, Joshua A. Sommers, Thomas A. Guilliam, Francesco Cucca, Daniel F. Bogenhagen, Alicia K. Byrd, Aidan J. Doherty, Stefania Bandinelli, Robert M. Brosh, Sanjay Kumar Bharti, Elena Yakubovskaya, Miguel Garcia-Diaz, Ann Zenobia Moore, Jun Ding, Kevin D. Raney |
| المصدر: | Hum Mol Genet |
| بيانات النشر: | Oxford University Press (OUP), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | DNA Replication, Mitochondrial DNA, Guanine, DNA Primase, DNA-Directed DNA Polymerase, DNA, Mitochondrial, Genome, DNA sequencing, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Genetics, Humans, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Whole Genome Sequencing, biology, DNA synthesis, DNA Helicases, DNA replication, Helicase, General Medicine, Multifunctional Enzymes, DNA Polymerase gamma, Mitochondria, Cell biology, G-Quadruplexes, Italy, chemistry, Mutagenesis, Genome, Mitochondrial, Mutation, biology.protein, Nucleic Acid Conformation, General Article, 030217 neurology & neurosurgery, DNA, Mitochondrial DNA replication |
| الوصف: | As the powerhouses of the eukaryotic cell, mitochondria must maintain their genomes which encode proteins essential for energy production. Mitochondria are characterized by guanine-rich DNA sequences that spontaneously form unusual three-dimensional structures known as G-quadruplexes (G4). G4 structures can be problematic for the essential processes of DNA replication and transcription because they deter normal progression of the enzymatic-driven processes. In this study, we addressed the hypothesis that mitochondrial G4 is a source of mutagenesis leading to base-pair substitutions. Our computational analysis of 2757 individual genomes from two Italian population cohorts (SardiNIA and InCHIANTI) revealed a statistically significant enrichment of mitochondrial mutations within sequences corresponding to stable G4 DNA structures. Guided by the computational analysis results, we designed biochemical reconstitution experiments and demonstrated that DNA synthesis by two known mitochondrial DNA polymerases (Pol γ, PrimPol) in vitro was strongly blocked by representative stable G4 mitochondrial DNA structures, which could be overcome in a specific manner by the ATP-dependent G4-resolving helicase Pif1. However, error-prone DNA synthesis by PrimPol using the G4 template sequence persisted even in the presence of Pif1. Altogether, our results suggest that genetic variation is enriched in G-quadruplex regions that impede mitochondrial DNA replication. |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5afb2d119be5d18078f77c07bad4b4f8Test https://doi.org/10.1093/hmg/ddaa043Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5afb2d119be5d18078f77c07bad4b4f8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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