Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons
| العنوان: | Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons |
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| المؤلفون: | Shivani Singh, Nayun Kim, Pedram Honarpisheh, Yaoxuan Wang, Liang Zhu, Akihiko Urayama, David Monchaud, Weiwei Dang, Jose F. Moruno-Manchon, Brenna S. McCauley, Andrey S. Tsvetkov, Louise D. McCullough, Diego A Morales Scheihing, Pauline Lejault |
| المساهمون: | University of Texas at Dallas [Richardson] (UT Dallas), Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC), Baylor College of Medicine (BCM), Baylor University |
| المصدر: | eLife eLife, eLife Sciences Publication, 2020, 9, ⟨10.7554/eLife.52283⟩ eLife, Vol 9 (2020) |
| بيانات النشر: | eLife Sciences Publications, Ltd, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Mouse, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Autophagy-Related Protein 7, Mice, 0302 clinical medicine, Transcription (biology), Biology (General), Picolinic Acids, Neurons, 0303 health sciences, biology, G-quadruplex, Chemistry, General Neuroscience, Neurodegeneration, neurodegeneration, Brain, General Medicine, 3. Good health, Cell biology, Aminoquinolines, Medicine, Research Article, autophagy, QH301-705.5, Science, Primary Cell Culture, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Animals, Humans, Gene, 030304 developmental biology, Memory Disorders, General Immunology and Microbiology, Autophagy, aging, Intron, DNA Helicases, Helicase, Cell Biology, medicine.disease, In vitro, Rats, G-Quadruplexes, Cancer cell, biology.protein, Rat, 030217 neurology & neurosurgery, Neuroscience |
| الوصف: | International audience; Guanine-rich DNA sequences can fold into four-stranded G-quadruplex (G4-DNA) structures. G4-DNA regulates replication and transcription, at least in cancer cells. Here, we demonstrate that, in neurons, pharmacologically stabilizing G4-DNA with G4 ligands strongly downregulates the Atg7 gene. Atg7 is a critical gene for the initiation of autophagy that exhibits decreased transcription with aging. Using an in vitro assay, we show that a putative G-quadruplex-forming sequence (PQFS) in the first intron of the Atg7 gene folds into a G4. An antibody specific to G4-DNA and the G4-DNA-binding protein PC4 bind to the Atg7 PQFS. Mice treated with a G4 stabilizer develop memory deficits. Brain samples from aged mice contain G4-DNA structures that are absent in brain samples from young mice. Overexpressing the G4-DNA helicase Pif1 in neurons exposed to the G4 stabilizer improves phenotypes associated with G4-DNA stabilization. Our findings indicate that G4-DNA is a novel pathway for regulating autophagy in neurons. |
| اللغة: | English |
| تدمد: | 2050-084X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::792d43f7b56f4ffe8e1a719b3196ae69Test http://europepmc.org/articles/PMC7012600Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....792d43f7b56f4ffe8e1a719b3196ae69 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2050084X |
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