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

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Cell Proliferation/*physiology ; Phosphoric Monoester Hydrolases/*metabolism; Animals ; DNA Damage ; DNA Repair ; Embryonic Development/genetics ; Embryonic Development/physiology ; Female ; Gene Knock-In Techniques ; Glycolates/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mice, Transgenic ; Mutant Proteins/genetics ; Mutant Proteins/metabolism ; Oxidation-Reduction ; Phosphatidylcholines/metabolism ; Phosphoric Monoester Hydrolases/antagonists & inhibitors ; Phosphoric Monoester Hydrolases/genetics ; Pregnancy ; Triglycerides/metabolism ; Triose-Phosphate Isomerase/metabolism

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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0 (Glycolates)
0 (Mutant Proteins)
0 (Phosphatidylcholines)
0 (Triglycerides)
EC 3.1.3.18 (phosphoglycolate phosphatase)
EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
EC 5.3.1.1 (Triose-Phosphate Isomerase)
H8593JOP13 (phosphoglycolate)

Date Created: 20161013 Date Completed: 20180424 Latest Revision: 20181113

20221213

PMC5059750

10.1038/srep35160

27731369