Regulation of DNA replication at the end of the mitochondrial D-loop involves the helicase TWINKLE and a conserved sequence element
Open accessAbstract
The majority of mitochondrial DNA replication events are terminated prematurely. The nascent DNA remains stably associated with the template, forming a triple-stranded displacement loop (D-loop) structure. However, the function of the D-loop region of the mitochondrial genome remains poorly understood. Using a comparative genomics approach we here identify two closely related 15 nt sequence motifs of the D-loop, strongly conserved among vertebrates. One motif is at the D-loop 5'-end and is part of the conserved sequence block 1 (CSB1). The other motif, here denoted coreTAS, is at the D-loop 3'-end. Both these sequences may prevent transcription across the D-loop region, since light and heavy strand transcription is terminated at CSB1 and coreTAS, respectively. Interestingly, the replication of the nascent D-loop strand, occurring in a direction opposite to that of heavy strand transcription, is also terminated at coreTAS, suggesting that coreTAS is involved in termination of both transcription and replication. Finally, we demonstrate that the loading of the helicase TWINKLE at coreTAS is reversible, implying that this site is a crucial component of a switch between D-loop formation and full-length mitochondrial DNA replication.
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The element within the D-loop region plays a crucial role in mediating the transition between mitochondrial DNA replication and transcription events.
“A previous report also indicates that the element within the D-loop region plays a crucial role in mediating the transition between mitochondrial DNA replication and transcription events. (Jemt et al, 2015).”
From The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer’s disease (2024) · cites this paper as Jemt et al, 2015
The Discussion reports that conserved D-loop elements appear to prevent transcription from entering the region, and that coreTAS may also influence DNA replication. It also suggests that replication and transcription termination at coreTAS may be coordinately regulated. It does not establish that the element mediates a transition between replication and transcription events. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTwinkle is involved in D-loop formation and localizes to the nucleoid.
“It is involved in D-loop formation and localizes to the nucleoid (Jemt et al., 2015; Milenkovic et al., 2013; Spelbrink et al., 2001).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Jemt et al., 2015
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- Authors
- Jemt, E., Persson, Ö., Shi, Y., Mehmedovic, M., Uhler, J. P., Dávila López, M., Freyer, C., Gustafsson, C. M., Samuelsson, T., & Falkenberg, M.
- Affiliations
- University of Gothenburg (SE)
- Karolinska Institutet (SE)
- Corresponding author
- Samuelsson, Tore
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-08-07
- Volume
- 43
- Issue
- 19
- Pages
- 9262-9275
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC4627069
- OpenAlex
- W1894198192
- Cited by
- 121
- References
- 63
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 18 · 2023: 10 · 2022: 15 · 2021: 9 · 2020: 10 · 2019: 12 · 2018: 6 · 2017: 7 · 2016: 10 · 2015: 1
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nucleic Acids Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Swedish Cancer Foundation
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Göteborgs Universitet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- mitochondrial DNA replication, D-loop, Twinkle helicase, replication termination, transcription termination, helicase loading
- MeSH terms
- Animals, Base Sequence, DNA Replication, DNA Helicases, DNA, Mitochondrial, HeLa Cells, Humans, Regulatory Sequences, Nucleic Acid, Vertebrates, Conserved Sequence, Signal Recognition Particle, RNA, Small Cytoplasmic, Mitochondrial Proteins, Mice, Inverted Repeat Sequences, Nucleotide Motifs, Transcription Termination, Genetic
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