Genesis and Wanderings: Origins and Migrations in Asymmetrically Replicating Mitochondrial DNA

Brown, Timothy A.; Clayton, David A.

doi:10.4161/cc.5.9.2710

Cited by 26 publications

(13 citation statements)

References 24 publications

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“…A link between the displacement of the O L and the occurrence of gene rearrangements was suggested since alternative initiation sites could give instability to the replication mechanism, resulting in such rearrangements (Macey et al, 1997). Additionally, it has been shown that some tRNA in primate mitochondria can potentially function as an alternative O L , which may reconcile much of the controversy regarding the strand-displacement model (Brown and Clayton, 2006). The thermodynamic stability of the O L has also been correlated with developmental stability in reptiles ).…”

Section: Introductionmentioning

confidence: 93%

Relationship between mitochondrial gene rearrangements and stability of the origin of light strand replication

Fonseca

Harris

2008

Genet. Mol. Biol.

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Mitochondrial gene rearrangements are much more frequent in vertebrates than initially thought. It has been suggested that the origin of light strand replication could have an important role in the process of gene rearrangements, but this hypothesis has never been tested before. We used amphibians to test the correlation between light-strand replication origin thermodynamic stability and the occurrence of gene rearrangements. The two variables were correlated in a non-phylogenetic approach, but when tested in a phylogenetically based comparative method the correlation was not significant, although species with unstable light-strand replication origins were much more likely to have undergone gene rearrangements. This indicates that within amphibians there are stable and unstable phylogenetic groups regarding mitochondrial gene order. The species analyzed showed variability in the thermodynamic stability of the secondary structure, in the length of its stem and loop, and several species did not present the 5'-GCCGG-3' motif reported to be necessary for efficient mitochondrial DNA replication. Future studies should focus on the role of the light-strand replication origin in mitochondrial DNA replication and gene rearrangements mechanisms.

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Section: Introductionmentioning

confidence: 93%

Relationship between mitochondrial gene rearrangements and stability of the origin of light strand replication

Fonseca

Harris

2008

Genet. Mol. Biol.

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“…Specifically, we have proposed that light-strand replication initiation can occur at various locations other than O L , as alternative light-strand origins ( alt O L ) (10,11). This alt O L modification of the standard model only requires, on occasion, a reduction in the asymmetry and a mechanism to initiate light-strand replication at locations other than O L .…”

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confidence: 99%

Native R-loops Persist throughout the Mouse Mitochondrial DNA Genome

Brown

Tkachuk

Clayton

2008

Journal of Biological Chemistry

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Mammalian mtDNA has been found here to harbor RNA-DNA hybrids at a variety of locations throughout the genome. The R-loop, previously characterized in vitro at the leading strand replication origin (O H ), is isolated as a native RNA-DNA hybrid copurifying with mtDNA. Surprisingly, other mitochondrial transcripts also form stable partial R-loops. These are abundant and affect mtDNA conformation. Current models regarding the mechanism of mammalian mtDNA replication have been expanded by recent data and discordant hypotheses. The presence of stable, nonreplicative, and partially hybridized RNA on the mtDNA template is significant for the reevaluation of replication models based on two-dimensional agarose gel analyses. In addition, the close association of a subpopulation of mtRNA with the DNA template has further implications regarding the structure, maintenance, and expression of the mitochondrial genome. These results demonstrate that variously processed and targeted mtRNAs within mammalian mitochondria likely have multiple functions in addition to their conventional roles.The normal fate of an RNA transcript is to exit the transcription complex and proceed to its functional site in the cell. An exception is the retention of the RNA paired to its DNA template complement as an RNA-DNA hybrid. These RNA-DNA hybrids, or R-loops, are typically found at origins of DNA replication. An early example of this phenomenon is the plasmid ColE1 replication origin in Escherichia coli, where R-loops are formed during transcription and then processed into shorter primers that sponsor DNA replication (1). A similar RNA-DNA hybrid is also utilized at the mammalian mtDNA replication origin, O H .2 Here, transcription from the light-strand promoter creates an RNA-DNA hybrid, which is a substrate for the endoribonuclease complex RNase MRP. The RNA processing sites for this nuclease coincide with RNA to DNA transitions, implicating a role in generating replication primers from the O H R-loop (2, 3). The R-loops at mtDNA origins from yeast, mouse, and human have been reconstituted and characterized in vitro (2, 4, 5).Replication of mammalian mtDNA proceeds by a displacement mode of replication utilizing origins that are strand-specific and asymmetrically positioned (Fig. 1). After initiation at O H , unidirectional synthesis proceeds along the template while displacing the opposite strand up to a distance of about twothirds around the 16-kb circular genome. Here, the nascent strand reaches the opposite strand-specific origin, O L , where synthesis of the second strand initiates. Elongation of the second strand then continues along the previously displaced single-stranded template in the opposite direction. Both strands are extended in an asymmetric manner until two daughter molecules are formed (6, 7).Recently, we and others have proposed alternative modes of mtDNA replication with initiation sites in addition to the sitespecific origins described initially (8 -11). Specifically, we have proposed that light-strand replication initiati...

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“…A recent study in which atomic force microscopy was used to examine mtDNA replicative intermediates in mouse liver was entirely consistent with the strand-displacement model, and did not show any evidence of the θ structures that would be predicted from the strand-coupled model 12 . The same study also provided evidence for alternative L-strand origins, and it was suggested that their presence, in addition to the propensity for branch migration in replicating DNA, might account for the patterns observed by 2-D gel electrophoresis that were interpreted as evidence for strand-coupled replication 13 .…”

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confidence: 77%