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| Status |
Public on Apr 30, 2019 |
| Title |
Implication of G-quadruplexes in mitochondrial gene expression and genome replication |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Single-stranded DNA or RNA sequences rich in guanine (G) can adopt non-canonical structures known as G-quadruplexes (G4). G4 in the mitochondrial genome are heavy-strand enriched and have been associated with the formation of deletion breakpoints that cause mitochondrial diseases. However, the functional role of G4 structures in mitochondria remains unclear. Here, we have identified RHPS4 as a G4-specific ligand that localizes to mitochondria and causes replication pausing, with mitochondrial DNA (mtDNA) depletion occurring at higher dosage. We further show that RHPS4 interferes with mitochondrial transcript elongation at low doses, leading to respiratory complex depletion. These unprecedented observations suggest that G4 motifs modulate mitochondrial transcription and replication efficiency. Using the differential effects of high vs low RHPS4 dosing, we characterized gene expression pathway responses to mitochondrial transcription inhibition or mitochondrial genome depletion. Importantly, a human mtDNA mutation that increases G4 formation potential strongly enhanced the RHPS4-mediated mitochondrial respiratory defect. We propose that abnormal G4 dynamics may contribute to mtDNA instability and gene expression defects, particularly in the presence of mitochondrial mutations that enhance the G4 formation.
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| Overall design |
Total RNA was extracted from the mouse embryonic fibroblasts (MEFs) stimulated with 0um (n=3), 2um (n=3), and 10um (n=2) RHPS4. Total stranded RNA libraries (ribo-depleted) were generated and sequenced on the Illumina NextSeq 500 NGS platform. RNA-seq data was analyzed for differentially expressed genes between groups of samples.
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| Contributor(s) |
Kaufman BA, Wang T |
| Citation(s) |
30944353 |
| |
| Submission date |
Aug 25, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Ting Wang |
| E-mail(s) |
wang9ting@gmail.com
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| Organization name |
Fred Hutchinson Cancer Research Center
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| Department |
Clinical Research
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| Street address |
1100 Fairview Ave. N.
|
| City |
Seattle |
| State/province |
WA |
| ZIP/Postal code |
98109 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA400210 |
| SRA |
SRP116194 |
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