DNA Sequences Proximal to Human Mitochondrial DNA Deletion Breakpoints Prevalent in Human Disease Form G-quadruplexes, a Class of DNA Structures Inefficiently Unwound by the Mitochondrial Replicative Twinkle Helicase

Bharti, Sanjay Kumar; Sommers, Joshua A.; Zhou, Jun; Kaplan, Daniel L.; Spelbrink, Johannes N.; Mergny, Jean‐Louis; Brosh, Robert M.

doi:10.1074/jbc.m114.567073

Cited by 118 publications

(109 citation statements)

References 101 publications

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“…Alternatively, or in addition, base substitution at guanines within G‐quartets may involve preferential oxidation during transcription, as a result of increased exposure to cellular oxidants while in their noncanonical duplex configuration [Clark et al., ; Zhou et al., ]. This latter model appears to be supported by the observation that, in mitochondrial DNA which is likely to come into contact with mitochondrial‐generated oxidants, deletion breakpoints are observed at high frequencies near G‐quartets [Bharti et al., ; Dong et al., ]. The occurrence of a mutation may either follow or precede unwinding of these G4 structures by DNA helicases, such as FANCJ [Wu et al., ], CHL1 [Wu et al., ], PIF1 [Sanders, ], or the recently characterized ATP‐dependent DEAH‐box helicase DHX36 [Chen et al., ].…”

Section: Resultsmentioning

confidence: 99%

A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease

et al. 2015

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Missense/nonsense mutations and micro-deletions/micro-insertions of <21bp together represent ~76% of all mutations causing human inherited disease. Previous studies have shown that their occurrence is influenced by sequences capable of non-B DNA formation (direct, inverted and mirror repeats; G-quartets). We found that a greater than expected proportion (~21%) of both micro-deletions and micro-insertions occur within direct repeats and are explicable by slipped misalignment. A novel mutational mechanism, non-B DNA triplex formation followed by DNA repair, is proposed to explain ~5% of micro-deletions and microinsertions at mirror repeats. Further, G-quadruplex-forming sequences, direct and inverted repeats appear to play a prominent role in mediating missense mutations, whereas only direct and inverted repeats mediate nonsense mutations. We suggest a mutational mechanism involving slipped strand mispairing, slipped structure formation and DNA repair, to explain ~15% of missense and ~12% of nonsense mutations leading to the formation of perfect direct repeats from imperfect repeats, or to the extension of existing direct repeats. Similar proportions of missense and nonsense mutations were explicable by the mechanism of hairpin loop formation and DNA repair leading to the formation of perfect inverted repeats from imperfect repeats. The proposed mechanisms provide new insights into mutagenesis underlying pathogenic micro-lesions.

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Section: Resultsmentioning

confidence: 99%

A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease

et al. 2015

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“…We also report that some regions of mtDNA, such as those with clusters of mt‐tRNA genes, seem to be particularly difficult sequences to bypass in the absence of TEFM, likely because of strong secondary structures. Recent computational analyses of the human mtDNA sequence suggest that there are ∼200 putative G‐quadruplex forming sequences , whose presence has been confirmed in live cells . The existence of G‐quadruplexes in the non‐transcribed DNA strand constitutes a very strong transcription barrier for a progressing RNA polymerase , and a G‐quadruplex in nascent RNA strongly stimulates transcription termination at CSBII .…”

Section: Discussionmentioning

confidence: 99%

TEFM regulates both transcription elongation and RNA processing in mitochondria

et al. 2019

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Regulation of replication and expression of mitochondrial DNA (mt DNA ) is essential for cellular energy conversion via oxidative phosphorylation. The mitochondrial transcription elongation factor ( TEFM ) has been proposed to regulate the switch between transcription termination for replication primer formation and processive, near genome‐length transcription for mt DNA gene expression. Here, we report that Tefm is essential for mouse embryogenesis and that levels of promoter‐distal mitochondrial transcripts are drastically reduced in conditional Tefm ‐knockout hearts. In contrast, the promoter‐proximal transcripts are much increased in Tefm knockout mice, but they mostly terminate before the region where the switch from transcription to replication occurs, and consequently, de novo mt DNA replication is profoundly reduced. Unexpectedly, deep sequencing of RNA from Tefm knockouts revealed accumulation of unprocessed transcripts in addition to defective transcription elongation. Furthermore, a proximity‐labeling (Bio ID ) assay showed that TEFM interacts with multiple RNA processing factors. Our data demonstrate that TEFM acts as a general transcription elongation factor, necessary for both gene transcription and replication primer formation, and loss of TEFM affects RNA processing in mammalian mitochondria.

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“…Human mtDNA contains 270 potential G4-forming sequences (52), many of which correlate with DNA breakpoints associated with diseases (52,78,79). It is of note that hypersensitive DNA cleavage sites have been described adjacent to G4DNA sequences in mitochondria (52,78,79) and proto-oncogenes (80,81).…”

Section: Discussionmentioning

confidence: 99%

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

Byrd¹,

Zybailov

Maddukuri³

et al. 2016

Journal of Biological Chemistry

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Cells engage numerous signaling pathways in response to oxidative stress that together repair macromolecular damage or direct the cell toward apoptosis. As a result of DNA damage, mitochondrial DNA or nuclear DNA has been shown to enter the cytoplasm where it binds to "DNA sensors," which in turn initiate signaling cascades. Here we report data that support a novel signaling pathway in response to oxidative stress mediated by specific guanine-rich sequences that can fold into G-quadruplex DNA (G4DNA). In response to oxidative stress, we demonstrate that sequences capable of forming G4DNA appear at increasing levels in the cytoplasm and participate in assembly of stress granules. Identified proteins that bind to endogenous G4DNA in the cytoplasm are known to modulate mRNA translation and participate in stress granule formation. Consistent with these findings, stress granule formation is known to regulate mRNA translation during oxidative stress. We propose a signaling pathway whereby cells can rapidly respond to DNA damage caused by oxidative stress. Guanine-rich sequences that are excised from damaged genomic DNA are proposed to enter the cytoplasm where they can regulate translation through stress granule formation. This newly proposed role for G4DNA provides an additional molecular explanation for why such sequences are prevalent in the human genome.

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DNA Sequences Proximal to Human Mitochondrial DNA Deletion Breakpoints Prevalent in Human Disease Form G-quadruplexes, a Class of DNA Structures Inefficiently Unwound by the Mitochondrial Replicative Twinkle Helicase

Cited by 118 publications

References 101 publications

A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease

A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease

TEFM regulates both transcription elongation and RNA processing in mitochondria

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

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