title: An essential developmental function for murine phosphoglycolate phosphatase in safeguarding cell proliferation.
abstract: 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 PgpD34Nmutant 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.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany.|Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Segerer
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany.|Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hadamek
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany.|Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Zundler
authors.affiliation: Institute of Pharmaceutical Biology, University of Würzburg, Julius-von-Sachs-Platz 2, D-97082 Würzburg, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Fekete
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany.|Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
authors.forename: Annegrit
authors.initials: A
authors.lastname: Seifried
authors.affiliation: Institute of Pharmaceutical Biology, University of Würzburg, Julius-von-Sachs-Platz 2, D-97082 Würzburg, Germany.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Mueller
authors.affiliation: Ozgene Pty Ltd, PO Box 1128, Bentley DC, WA 6983, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Koentgen
authors.affiliation: Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, Am Hubland, University of Würzburg, D-97074 Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Strasse 6, D-97080 Würzburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Gessler
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany.|Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jeanclos
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany.|Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Gohla
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D004249:DNA Damage; D004260:DNA Repair; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D005260:Female; D055879:Gene Knock-In Techniques; D006016:Glycolates / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010713:Phosphatidylcholines / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D014280:Triglycerides / Q000378:metabolism; D014305:Triose-Phosphate Isomerase / Q000378:metabolism
chemical_list: D006016:Glycolates; D050505:Mutant Proteins; D010713:Phosphatidylcholines; D014280:Triglycerides; C022408:phosphoglycolate phosphatase; D010744:Phosphoric Monoester Hydrolases; D014305:Triose-Phosphate Isomerase; C013193:phosphoglycolate