G-quadruplex dynamics contribute to regulation of mitochondrial gene expression
| Autor: | Patrick J. Pagano, Neal Sondheimer, Jill E. Kolesar, L. Sun, Y. V. Taguchi, Jonathan K. Alder, Chih-Hsien Wang, F. B. Johnson, J. Turek-Herman, Ting Wang, D.S. de Jesus, C. St. Croix, W. Horne, Liliya A. Yatsunyk, Callen T. Wallace, Micol Falabella, I. M. Xiang, R. Maheshan, Brett A. Kaufman |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
DNA Replication
0301 basic medicine Mitochondrial DNA Guanine Gene Expression lcsh:Medicine Mitochondrion DNA Mitochondrial Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Transcription (biology) Cell Line Tumor Animals Humans Respiratory function lcsh:Science Cells Cultured Sequence Deletion Mice Inbred BALB C Multidisciplinary lcsh:R Processivity Mitochondria 3. Good health Nuclear DNA Cell biology G-Quadruplexes Genes Mitochondrial 030104 developmental biology chemistry Genome Mitochondrial Nucleic acid lcsh:Q 030217 neurology & neurosurgery DNA HeLa Cells |
| Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-17 (2019) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-41464-y |
| Popis: | Single-stranded DNA or RNA sequences rich in guanine (G) can adopt non-canonical structures known as G-quadruplexes (G4). Mitochondrial DNA (mtDNA) sequences that are predicted to form G4 are enriched on the heavy-strand and have been associated with formation of deletion breakpoints. Increasing evidence supports the ability of mtDNA to form G4 in cancer cells; however, the functional roles of G4 structures in regulating mitochondrial nucleic acid homeostasis in non-cancerous cells remain unclear. Here, we demonstrate by live cell imaging that the G4-ligand RHPS4 localizes primarily to mitochondria at low doses. We find that low doses of RHPS4 do not induce a nuclear DNA damage response but do cause an acute inhibition of mitochondrial transcript elongation, leading to respiratory complex depletion. We also observe that RHPS4 interferes with mtDNA levels or synthesis both in cells and isolated mitochondria. Importantly, a mtDNA variant that increases G4 stability and anti-parallel G4-forming character shows a stronger respiratory defect in response to RHPS4, supporting the conclusion that mitochondrial sensitivity to RHPS4 is G4-mediated. Taken together, our results indicate a direct role for G4 perturbation in mitochondrial genome replication, transcription processivity, and respiratory function in normal cells. |
| Databáze: | OpenAIRE |
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