Mitochondrial genetic variation is enriched in G-quadruplex regions that stall DNA synthesis in vitro.
DNA Helicases
/ genetics
DNA Polymerase gamma
/ genetics
DNA Primase
/ genetics
DNA Replication
/ genetics
DNA, Mitochondrial
/ genetics
DNA-Directed DNA Polymerase
/ genetics
G-Quadruplexes
Genome, Mitochondrial
/ genetics
Guanine
/ metabolism
Humans
Italy
Mitochondria
/ genetics
Multifunctional Enzymes
/ genetics
Mutagenesis
/ genetics
Mutation
/ genetics
Nucleic Acid Conformation
Whole Genome Sequencing
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
28 05 2020
28 05 2020
Historique:
received:
13
11
2019
revised:
27
01
2020
accepted:
18
03
2020
pubmed:
20
3
2020
medline:
7
8
2021
entrez:
20
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32191790
pii: 5810180
doi: 10.1093/hmg/ddaa043
pmc: PMC7254849
doi:
Substances chimiques
DNA, Mitochondrial
0
Multifunctional Enzymes
0
Guanine
5Z93L87A1R
DNA Primase
EC 2.7.7.-
PrimPol protein, human
EC 2.7.7.-
DNA Polymerase gamma
EC 2.7.7.7
DNA-Directed DNA Polymerase
EC 2.7.7.7
DNA Helicases
EC 3.6.4.-
PIF1 protein, human
EC 5.99.-
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1292-1309Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/H019723/1
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM112790
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM122601
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M008800/1
Pays : United Kingdom
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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