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Mitochondrial genetic variation is enriched in G-quadruplex regions that stall DNA synthesis in vitro.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2020 May 28; Vol. 29 (8), pp. 1292-1309. - Publication Year :
- 2020
-
Abstract
- 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.<br /> (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- DNA, Mitochondrial genetics
Genome, Mitochondrial genetics
Guanine metabolism
Humans
Italy
Mitochondria genetics
Mutagenesis genetics
Mutation genetics
Nucleic Acid Conformation
Whole Genome Sequencing
DNA Helicases genetics
DNA Polymerase gamma genetics
DNA Primase genetics
DNA Replication genetics
DNA-Directed DNA Polymerase genetics
G-Quadruplexes
Multifunctional Enzymes genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 29
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 32191790
- Full Text :
- https://doi.org/10.1093/hmg/ddaa043