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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
- Source :
- Journal of Biological Chemistry, 289, 43, pp. 29975-93, Journal of Biological Chemistry, 289, 29975-93
- Publication Year :
- 2014
-
Abstract
- Contains fulltext : 138677.pdf (Publisher’s version ) (Open Access) Mitochondrial DNA deletions are prominent in human genetic disorders, cancer, and aging. It is thought that stalling of the mitochondrial replication machinery during DNA synthesis is a prominent source of mitochondrial genome instability; however, the precise molecular determinants of defective mitochondrial replication are not well understood. In this work, we performed a computational analysis of the human mitochondrial genome using the "Pattern Finder" G-quadruplex (G4) predictor algorithm to assess whether G4-forming sequences reside in close proximity (within 20 base pairs) to known mitochondrial DNA deletion breakpoints. We then used this information to map G4P sequences with deletions characteristic of representative mitochondrial genetic disorders and also those identified in various cancers and aging. Circular dichroism and UV spectral analysis demonstrated that mitochondrial G-rich sequences near deletion breakpoints prevalent in human disease form G-quadruplex DNA structures. A biochemical analysis of purified recombinant human Twinkle protein (gene product of c10orf2) showed that the mitochondrial replicative helicase inefficiently unwinds well characterized intermolecular and intramolecular G-quadruplex DNA substrates, as well as a unimolecular G4 substrate derived from a mitochondrial sequence that nests a deletion breakpoint described in human renal cell carcinoma. Although G4 has been implicated in the initiation of mitochondrial DNA replication, our current findings suggest that mitochondrial G-quadruplexes are also likely to be a source of instability for the mitochondrial genome by perturbing the normal progression of the mitochondrial replication machinery, including DNA unwinding by Twinkle helicase.
- Subjects :
- DNA Replication
Aging
Mitochondrial DNA
Ultraviolet Rays
Base pair
Molecular Sequence Data
DNA and Chromosomes
Biology
Nucleic Acid Denaturation
MT-RNR1
DNA, Mitochondrial
Biochemistry
Human mitochondrial genetics
Substrate Specificity
Evolution, Molecular
Mitochondrial Proteins
Neoplasms
Animals
Humans
Disease
Nucleotide Motifs
Molecular Biology
Conserved Sequence
Sequence Deletion
Genetics
Homoplasmy
Base Sequence
Circular Dichroism
DNA Helicases
DNA replication
Computational Biology
Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6]
Cell Biology
Telomere
Recombinant Proteins
Mitochondria
G-Quadruplexes
Genome, Mitochondrial
DNAJA3
DNA Damage
Mitochondrial DNA replication
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 289
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....e403b335d3a9f6c4878c968e8e9c3416