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Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons
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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012600/ https://www.ncbi.nlm.nih.gov/pubmed/32043463 http://dx.doi.org/10.7554/eLife.52283 |
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author | Moruno-Manchon, Jose F Lejault, Pauline Wang, Yaoxuan McCauley, Brenna Honarpisheh, Pedram Morales Scheihing, Diego A Singh, Shivani Dang, Weiwei Kim, Nayun Urayama, Akihiko Zhu, Liang Monchaud, David McCullough, Louise D Tsvetkov, Andrey S |
author_facet | Moruno-Manchon, Jose F Lejault, Pauline Wang, Yaoxuan McCauley, Brenna Honarpisheh, Pedram Morales Scheihing, Diego A Singh, Shivani Dang, Weiwei Kim, Nayun Urayama, Akihiko Zhu, Liang Monchaud, David McCullough, Louise D Tsvetkov, Andrey S |
author_sort | Moruno-Manchon, Jose F |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7012600 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-70126002020-02-12 Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons Moruno-Manchon, Jose F Lejault, Pauline Wang, Yaoxuan McCauley, Brenna Honarpisheh, Pedram Morales Scheihing, Diego A Singh, Shivani Dang, Weiwei Kim, Nayun Urayama, Akihiko Zhu, Liang Monchaud, David McCullough, Louise D Tsvetkov, Andrey S eLife Cell Biology 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. eLife Sciences Publications, Ltd 2020-02-11 /pmc/articles/PMC7012600/ /pubmed/32043463 http://dx.doi.org/10.7554/eLife.52283 Text en © 2020, Moruno-Manchon et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Moruno-Manchon, Jose F Lejault, Pauline Wang, Yaoxuan McCauley, Brenna Honarpisheh, Pedram Morales Scheihing, Diego A Singh, Shivani Dang, Weiwei Kim, Nayun Urayama, Akihiko Zhu, Liang Monchaud, David McCullough, Louise D Tsvetkov, Andrey S Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons |
title | Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons |
title_full | Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons |
title_fullStr | Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons |
title_full_unstemmed | Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons |
title_short | Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons |
title_sort | small-molecule g-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012600/ https://www.ncbi.nlm.nih.gov/pubmed/32043463 http://dx.doi.org/10.7554/eLife.52283 |
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