Ribonucleotides in mitochondrial <scp>DNA</scp>

Wanrooij, Paulina H.; Chabes, Andrei

doi:10.1002/1873-3468.13440

Cited by 16 publications

(16 citation statements)

References 100 publications

(171 reference statements)

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“…In contrast to nDNA, mtDNA contains persistent rNMPs that are not removed after incorporation by the replicative mtDNA polymerase Pol γ (reviewed in ref. 19). Human Pol γ is highly selective against using rNTPs as substrates and thus incorporates fewer rNMPs than nuclear replicative DNA polymerases do (20)(21)(22).…”

Section: Samhd1mentioning

confidence: 99%

Elimination of rNMPs from mitochondrial DNA has no effect on its stability

Wanrooij

Tran

Thompson

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Ribonucleotides (rNMPs) incorporated in the nuclear genome are a well-established threat to genome stability and can result in DNA strand breaks when not removed in a timely manner. However, the presence of a certain level of rNMPs is tolerated in mitochondrial DNA (mtDNA) although aberrant mtDNA rNMP content has been identified in disease models. We investigated the effect of incorporated rNMPs on mtDNA stability over the mouse life span and found that the mtDNA rNMP content increased during early life. The rNMP content of mtDNA varied greatly across different tissues and was defined by the rNTP/dNTP ratio of the tissue. Accordingly, mtDNA rNMPs were nearly absent inSAMHD1−/−mice that have increased dNTP pools. The near absence of rNMPs did not, however, appreciably affect mtDNA copy number or the levels of mtDNA molecules with deletions or strand breaks in aged animals near the end of their life span. The physiological rNMP load therefore does not contribute to the progressive loss of mtDNA quality that occurs as mice age.

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Section: Samhd1mentioning

confidence: 99%

Elimination of rNMPs from mitochondrial DNA has no effect on its stability

Wanrooij

Tran

Thompson

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…The human mitochondrial DNA (mtDNA) is a circular multicopy molecule of 16.5 kb, composed of two filaments, named heavy (H) strand and light (L) strand, and whose replication mechanism is not completely resolved. Different models for mitochondrial DNA duplication have been proposed, which are well described in recent reviews [152,153]; here, we only summarized the types and the sources of rNMPs that could be found into mtDNA (reviewed in [154]).…”

Section: Ribonucleotides Into the Dna Of Organellesmentioning

confidence: 99%

One, No One, and One Hundred Thousand: The Many Forms of Ribonucleotides in DNA

Nava

Grasso

Sertic

et al. 2020

IJMS

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In the last decade, it has become evident that RNA is frequently found in DNA. It is now well established that single embedded ribonucleoside monophosphates (rNMPs) are primarily introduced by DNA polymerases and that longer stretches of RNA can anneal to DNA, generating RNA:DNA hybrids. Among them, the most studied are R-loops, peculiar three-stranded nucleic acid structures formed upon the re-hybridization of a transcript to its template DNA. In addition, polyribonucleotide chains are synthesized to allow DNA replication priming, double-strand breaks repair, and may as well result from the direct incorporation of consecutive rNMPs by DNA polymerases. The bright side of RNA into DNA is that it contributes to regulating different physiological functions. The dark side, however, is that persistent RNA compromises genome integrity and genome stability. For these reasons, the characterization of all these structures has been under growing investigation. In this review, we discussed the origin of single and multiple ribonucleotides in the genome and in the DNA of organelles, focusing on situations where the aberrant processing of RNA:DNA hybrids may result in multiple rNMPs embedded in DNA. We concluded by providing an overview of the currently available strategies to study the presence of single and multiple ribonucleotides in DNA in vivo.

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“…oxidized, alkylated or deaminated) nucleotides, incorporated ribonucleotides, secondary structures (e.g. G-quadruplexes), UV-light induced lesions, and topological stress in the template, as well as from an insufficient or unbalanced nucleotide pool (34,69,111,170,181). The mitochondrial replisome can also be challenged by pathological mutations in its components (33,173).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA Instability in Mammalian Cells

Carvalho

Repolês

Mendes

et al. 2022

Antioxidants & Redox Signaling

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Significance: The small, multicopy mitochondrial genome (mtDNA) is essential for efficient energy production, as alterations in its coding information or a decrease in its copy number disrupt mitochondrial ATP synthesis. However, the mitochondrial replication machinery encounters numerous challenges that may limit its ability to duplicate this important genome and that jeopardize mtDNA stability, including various lesions in the DNA template, topological stress and an insufficient nucleotide supply.Recent Advances: An ever-growing array of DNA repair or maintenance factors are being reported to localize to the mitochondria. We review current knowledge regarding the mitochondrial factors that may contribute to the tolerance or repair of various types of changes in the mitochondrial genome, such as base damage, incorporated ribonucleotides and strand breaks. We also discuss the newly-discovered link between mtDNA instability and activation of the innate immune response. Critical Issues: By which mechanisms do mitochondria respond to challenges that threaten mtDNA maintenance? What types of mtDNA damage are repaired, and when are the affected molecules degraded instead? And, finally, which forms of mtDNA instability trigger an immune response, and how? Future Directions: Further work is required to understand the contribution of the DNA repair and damage-tolerance factors present in the mitochondrial compartment, as well as the balance between mtDNA repair and degradation. Finally, efforts to understand the events underlying mtDNA release into the cytosol are warranted. Pursuing these and many related avenues can improve our understanding of what goes wrong in mitochondrial disease.

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Ribonucleotides in mitochondrial DNA

Cited by 16 publications

References 100 publications

Elimination of rNMPs from mitochondrial DNA has no effect on its stability

Elimination of rNMPs from mitochondrial DNA has no effect on its stability

One, No One, and One Hundred Thousand: The Many Forms of Ribonucleotides in DNA

Mitochondrial DNA Instability in Mammalian Cells

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