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A Conserved Mechanism for Hormesis in Molecular Systems

Hormesis refers to dose-response phenomena where low dose treatments elicit a response that is opposite the response observed at higher doses. Hormetic dose-response relationships have been observed throughout all of biology, but the underlying determinants of many reported hormetic dose-responses h...

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Autores principales: Greenwood, Sharon N., Belz, Regina G., Weiser, Brian P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9350523/
https://www.ncbi.nlm.nih.gov/pubmed/35936511
http://dx.doi.org/10.1177/15593258221109335
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author Greenwood, Sharon N.
Belz, Regina G.
Weiser, Brian P.
author_facet Greenwood, Sharon N.
Belz, Regina G.
Weiser, Brian P.
author_sort Greenwood, Sharon N.
collection PubMed
description Hormesis refers to dose-response phenomena where low dose treatments elicit a response that is opposite the response observed at higher doses. Hormetic dose-response relationships have been observed throughout all of biology, but the underlying determinants of many reported hormetic dose-responses have not been identified. In this report, we describe a conserved mechanism for hormesis on the molecular level where low dose treatments enhance a response that becomes reduced at higher doses. The hormetic mechanism relies on the ability of protein homo-multimers to simultaneously interact with a substrate and a competitor on different subunits at low doses of competitor. In this case, hormesis can be observed if simultaneous binding of substrate and competitor enhances a response of the homo-multimer. We characterized this mechanism of hormesis in binding experiments that analyzed the interaction of homotrimeric proliferating cell nuclear antigen (PCNA) with uracil DNA glycosylase (UNG2) and a fluorescein-labeled peptide. Additionally, the basic features of this molecular mechanism appear to be conserved with at least two enzymes that are stimulated by low doses of inhibitor: dimeric BRAF and octameric glutamine synthetase 2 (GS2). Identifying such molecular mechanisms of hormesis may help explain specific hormetic responses of cells and organisms treated with exogenous compounds.
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spelling pubmed-93505232022-08-05 A Conserved Mechanism for Hormesis in Molecular Systems Greenwood, Sharon N. Belz, Regina G. Weiser, Brian P. Dose Response Original Article Hormesis refers to dose-response phenomena where low dose treatments elicit a response that is opposite the response observed at higher doses. Hormetic dose-response relationships have been observed throughout all of biology, but the underlying determinants of many reported hormetic dose-responses have not been identified. In this report, we describe a conserved mechanism for hormesis on the molecular level where low dose treatments enhance a response that becomes reduced at higher doses. The hormetic mechanism relies on the ability of protein homo-multimers to simultaneously interact with a substrate and a competitor on different subunits at low doses of competitor. In this case, hormesis can be observed if simultaneous binding of substrate and competitor enhances a response of the homo-multimer. We characterized this mechanism of hormesis in binding experiments that analyzed the interaction of homotrimeric proliferating cell nuclear antigen (PCNA) with uracil DNA glycosylase (UNG2) and a fluorescein-labeled peptide. Additionally, the basic features of this molecular mechanism appear to be conserved with at least two enzymes that are stimulated by low doses of inhibitor: dimeric BRAF and octameric glutamine synthetase 2 (GS2). Identifying such molecular mechanisms of hormesis may help explain specific hormetic responses of cells and organisms treated with exogenous compounds. SAGE Publications 2022-08-02 /pmc/articles/PMC9350523/ /pubmed/35936511 http://dx.doi.org/10.1177/15593258221109335 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Article
Greenwood, Sharon N.
Belz, Regina G.
Weiser, Brian P.
A Conserved Mechanism for Hormesis in Molecular Systems
title A Conserved Mechanism for Hormesis in Molecular Systems
title_full A Conserved Mechanism for Hormesis in Molecular Systems
title_fullStr A Conserved Mechanism for Hormesis in Molecular Systems
title_full_unstemmed A Conserved Mechanism for Hormesis in Molecular Systems
title_short A Conserved Mechanism for Hormesis in Molecular Systems
title_sort conserved mechanism for hormesis in molecular systems
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9350523/
https://www.ncbi.nlm.nih.gov/pubmed/35936511
http://dx.doi.org/10.1177/15593258221109335
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