Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions

Persson, Örjan; Muthukumar, Yazh; Basu, Swaraj; Jenninger, Louise; Uhler, Jay P.; Berglund, Anders; McFarland, Robert; Taylor, Robert W.; Gustafsson, Claes M.; Larsson, Erik; Falkenberg, Maria

doi:10.1038/s41467-019-08673-5

Cited by 45 publications

(84 citation statements)

References 34 publications

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“…Despite the fact that PRDM9 is not officially included into the mitoproteome (Calvo, Clauser, and Mootha 2016) , the similarity is striking. Also, the motif of the common repeat is highly C-rich (8 out of 13) which is a hallmark of highly mutagenic repeats (Persson et al 2019) .…”

Section: The Motif Of the Common Repeat Can Be Associated With Specifmentioning

confidence: 99%

“…And thus this nonuniformity requires a special explanation. Drawing parallels with bacterial deletions (Albertini et al 1982) , experiments with mtDNA common repeat (Persson et al 2019) and…”

Section: The Most Mutagenic Region Of the Major Arc -Effect Of The Comentioning

confidence: 99%

“…According to the most recent model (Persson et al 2019) , mtDNA deletions originate during mtDNA replication when a long stretch of the major arc (specifically -the parental heavy chain) is single-stranded. Thus, using the potential contact of the Hi-C matrix (Fig 2A) exclusively as a suggestive one, in the downstream analyses we focus on the reconstruction of the secondary structure of the single-stranded mtDNA during replication.…”

Section: Major Arc Of Mtdna May Be Folded Into the Large-scale Loops:mentioning

confidence: 99%

“…This result is in line with the previous observation of Samuels et al (Samuels, Schon, and Chinnery 2004) and confirms that direct repeats alone poorly explain the distribution of the deletions. There is also a possibility that deletions are induced by the special motifs -for example, it has been shown that repeats inducing deletions are more C-rich (Persson et al 2019) . Thus, the shifted distribution of deletions might be explained by the shifted distribution of such motifs.…”

Section: Single-stranded Heavy Chain Of the Major Arc May Have Secondmentioning

confidence: 99%

“…The process of replication slippage, which is also called a copy-choice recombination, has been shown to affect deletion formation in bacteria (Viguera, Canceill, and Ehrlich 2001;Albertini et al 1982) and in experimental templates simulating mtDNA in vitro (Persson et al 2019) . It is based on the (i) arrest of replication due to the secondary structure formed by the inverted repeats on single-stranded DNA (ii), dissociation of the newly synthesized (nascent) proximal arm of the direct repeat and (iii) realigning of the nascent arm to the distal parental one ( Fig 3A).…”

Section: Deletions Are More Frequent If Direct Repeats Are Nested Witmentioning

confidence: 99%

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Risk of mitochondrial deletions is affected by the global secondary structure of the human mitochondrial genome

Mikhailova

Shamanskiy

Ushakova

et al. 2019

Preprint

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Aging is associated with accumulation of somatic mutations . This process is especially pronounced in mitochondrial genomes (mtDNA) of postmitotic cells, where accumulation of large-scale somatic mitochondrial deletions is associated with age-related mitochondrial encephalomyopathies. Here we revise risks of somatic mtDNA deletions and uncover that additionally to direct repeats, known to affect deletions, there is a strong impact of the secondary structure of single-stranded mtDNA during replication. The secondary structure is shaped by inverted repeats which can form stems and shorten effective distance between two direct repeats increasing chances of deletions. Our results support recent discovery that the replication slippage can be the main mechanism of origin of mtDNA deletions. Taking into account strong interaction between direct and inverted repeats it is possible to predict the deletion burden of different haplogroups and associate it with age-related phenotypes. For example, the increased longevity of D4a and D5a haplogroups is in line with their expected low deletion burden.

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Section: The Motif Of the Common Repeat Can Be Associated With Specifmentioning

confidence: 99%

Section: The Most Mutagenic Region Of the Major Arc -Effect Of The Comentioning

confidence: 99%

Section: Major Arc Of Mtdna May Be Folded Into the Large-scale Loops:mentioning

confidence: 99%

Section: Single-stranded Heavy Chain Of the Major Arc May Have Secondmentioning

confidence: 99%

Section: Deletions Are More Frequent If Direct Repeats Are Nested Witmentioning

confidence: 99%

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Risk of mitochondrial deletions is affected by the global secondary structure of the human mitochondrial genome

Mikhailova

Shamanskiy

Ushakova

et al. 2019

Preprint

View full text Add to dashboard Cite

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Skeletal muscle mitochondrial DNA copy number and mitochondrial DNA deletion mutation frequency as predictors of physical performance in older men and women

et al. 2021

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Mitochondrial DNA (mtDNA) quality and quantity relate to two hallmarks of aging-genomic instability and mitochondrial dysfunction. Physical performance relies on mitochondrial integrity and declines with age, yet the interactions between mtDNA quantity, quality, and physical performance are unclear. Using a validated digital PCR assay specific for mtDNA deletions, we tested the hypothesis that skeletal muscle mtDNA deletion mutation frequency (i.e., a measure of mtDNA quality) or mtDNA copy number predicts physical performance in older adults. Total DNA was isolated from vastus lateralis muscle biopsies and used to quantitate mtDNA copy number and mtDNA deletion frequency by digital PCR. The biopsies were obtained from a cross-sectional cohort of 53 adults aged 50 to 86 years. Before the biopsy procedure, physical performance measurements were collected, including VO 2max , modified physical performance test score, 6-min walk distance, gait speed, grip strength, and total lean and leg mass. Linear regression models were used to evaluate the relationships between age, sex, and the outcomes. We found that mtDNA deletion mutation frequency increased exponentially with advancing age. On average from ages 50 to 86, deletion frequency increased from

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Decoding the mitochondria without a code: mechanistic insights into mitochondrial DNA depletion syndromes

Sen,

Jetto,

Manjithaya

2024

J Biosci

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Copy-choice recombination during mitochondrial L-strand synthesis causes DNA deletions

Cited by 45 publications

References 34 publications

Risk of mitochondrial deletions is affected by the global secondary structure of the human mitochondrial genome

Risk of mitochondrial deletions is affected by the global secondary structure of the human mitochondrial genome

Skeletal muscle mitochondrial DNA copy number and mitochondrial DNA deletion mutation frequency as predictors of physical performance in older men and women

Decoding the mitochondria without a code: mechanistic insights into mitochondrial DNA depletion syndromes

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