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An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation

Mammalian phosphoglycolate phosphatase (PGP) is thought to target phosphoglycolate, a 2-deoxyribose fragment derived from the repair of oxidative DNA lesions. However, the physiological role of this activity and the biological function of the DNA damage product phosphoglycolate is unknown. We now sh...

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Autores principales: Segerer, Gabriela, Hadamek, Kerstin, Zundler, Matthias, Fekete, Agnes, Seifried, Annegrit, Mueller, Martin J., Koentgen, Frank, Gessler, Manfred, Jeanclos, Elisabeth, Gohla, Antje
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059750/
https://www.ncbi.nlm.nih.gov/pubmed/27731369
http://dx.doi.org/10.1038/srep35160
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author Segerer, Gabriela
Hadamek, Kerstin
Zundler, Matthias
Fekete, Agnes
Seifried, Annegrit
Mueller, Martin J.
Koentgen, Frank
Gessler, Manfred
Jeanclos, Elisabeth
Gohla, Antje
author_facet Segerer, Gabriela
Hadamek, Kerstin
Zundler, Matthias
Fekete, Agnes
Seifried, Annegrit
Mueller, Martin J.
Koentgen, Frank
Gessler, Manfred
Jeanclos, Elisabeth
Gohla, Antje
author_sort Segerer, Gabriela
collection PubMed
description Mammalian phosphoglycolate phosphatase (PGP) is thought to target phosphoglycolate, a 2-deoxyribose fragment derived from the repair of oxidative DNA lesions. However, the physiological role of this activity and the biological function of the DNA damage product phosphoglycolate is unknown. We now show that knockin replacement of murine Pgp with its phosphatase-inactive Pgp(D34N) mutant is embryonically lethal due to intrauterine growth arrest and developmental delay in midgestation. PGP inactivation attenuated triosephosphate isomerase activity, increased triglyceride levels at the expense of the cellular phosphatidylcholine content, and inhibited cell proliferation. These effects were prevented under hypoxic conditions or by blocking phosphoglycolate release from damaged DNA. Thus, PGP is essential to sustain cell proliferation in the presence of oxygen. Collectively, our findings reveal a previously unknown mechanism coupling a DNA damage repair product to the control of intermediary metabolism and cell proliferation.
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spelling pubmed-50597502016-10-24 An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation Segerer, Gabriela Hadamek, Kerstin Zundler, Matthias Fekete, Agnes Seifried, Annegrit Mueller, Martin J. Koentgen, Frank Gessler, Manfred Jeanclos, Elisabeth Gohla, Antje Sci Rep Article Mammalian phosphoglycolate phosphatase (PGP) is thought to target phosphoglycolate, a 2-deoxyribose fragment derived from the repair of oxidative DNA lesions. However, the physiological role of this activity and the biological function of the DNA damage product phosphoglycolate is unknown. We now show that knockin replacement of murine Pgp with its phosphatase-inactive Pgp(D34N) mutant is embryonically lethal due to intrauterine growth arrest and developmental delay in midgestation. PGP inactivation attenuated triosephosphate isomerase activity, increased triglyceride levels at the expense of the cellular phosphatidylcholine content, and inhibited cell proliferation. These effects were prevented under hypoxic conditions or by blocking phosphoglycolate release from damaged DNA. Thus, PGP is essential to sustain cell proliferation in the presence of oxygen. Collectively, our findings reveal a previously unknown mechanism coupling a DNA damage repair product to the control of intermediary metabolism and cell proliferation. Nature Publishing Group 2016-10-12 /pmc/articles/PMC5059750/ /pubmed/27731369 http://dx.doi.org/10.1038/srep35160 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Segerer, Gabriela
Hadamek, Kerstin
Zundler, Matthias
Fekete, Agnes
Seifried, Annegrit
Mueller, Martin J.
Koentgen, Frank
Gessler, Manfred
Jeanclos, Elisabeth
Gohla, Antje
An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation
title An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation
title_full An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation
title_fullStr An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation
title_full_unstemmed An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation
title_short An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation
title_sort essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059750/
https://www.ncbi.nlm.nih.gov/pubmed/27731369
http://dx.doi.org/10.1038/srep35160
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