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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
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.
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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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