ArticleHuman molecular genetics2020
Mitochondrial genetic variation is enriched in G-quadruplex regions that stall DNA synthesis in vitro.
Article in Human molecular genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 56 citations in OpenAlex.
- Rare genetic diseases associated with G-quadruplex-induced replication stress.Communications biology · 2026Review
- Non-B DNA structures and their contributions to genetic diversity, aging, and disease.Nucleic acids research · 2026Review
- Age-associated G-quadruplex accumulation and DDX5 loss shape chromatin landscapes in human astrocytes.Research square · 2025Article
- Untargeted CUT&Tag reads are enriched at accessible chromatin and restrict identification of potential G4-forming sequences in G4-targeted CUT&Tag experiments.Nucleic acids research · 2025Article
- Accurate DNA Synthesis Across 8-Oxoadenine by Human PrimPol.International journal of molecular sciences · 2025Article
- The effect of prolonged G-quadruplex stabilization on the functions of human cells.Scientific reports · 2025Article
- DNA synthesis across DNA hairpins by human PrimPol.DNA repair · 2024Article
- Two residues in the DNA binding site of Pif1 helicase are essential for nuclear functions but dispensable for mitochondrial respiratory growth.Nucleic acids research · 2024Article
- G-quadruplex propensity inNAR genomics and bioinformatics · 2024Article
- Genomic Instability of G-Quadruplex Sequences inGenes · 2023Article
- Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells.Nucleic acids research · 2023Article
- G-quadruplex ligands as potent regulators of lysosomes.Autophagy · 2023Article
- Mapping mitonuclear epistasis using a novel recombinant yeast population.PLoS genetics · 2023Article
- Noncanonical DNA structures are drivers of genome evolution.Trends in genetics : TIG · 2023Review
- Article
- Biochemical analysis of DNA synthesis blockage by G-quadruplex structure and bypass facilitated by a G4-resolving helicase.Methods (San Diego, Calif.) · 2022Article
- Role and Regulation of Pif1 Family Helicases at the Replication Fork.International journal of molecular sciences · 2022Review
- Review
- G-quadruplex DNA: a novel target for drug design.Cellular and molecular life sciences : CMLS · 2021Review
- PRIMPOL ready, set, reprime!Critical reviews in biochemistry and molecular biology · 2021Review
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Authors and funding
21 authors at 7 institutions in 3 countries.
Funding
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.
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