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

Gabriela Segerer,Agnes Fekete,Matthias Zundler,Elisabeth Jeanclos,Martin J Mueller,Frank Koentgen,Manfred Gessler,Annegrit Seifried,Kerstin Hadamek,Antje Gohla

doi:10.1038/srep35160

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 PgpD34N 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.

Highlights

Three orders of magnitude higher than towards Gro3P11, prompting us to genetically explore the physiological functions of PGP activity in mice
By quantitative real-time PCR (qPCR), we found that Dgat[2] RNA expression levels were more than doubled in E8.5 PGP-inactivated embryos compared to their wildtype counterparts, whereas Dgat[1] expression was unchanged (Fig. 4f)
Since PG is released from oxidatively damaged DNA termini bearing 3′-phosphoglycolate ends, which can be repaired by tyrosyl DNA phosphodiesterase-1 (TDP1)[2,3,6,7,31], we examined the impact of TDP1 inhibition

Summary

Introduction

Three orders of magnitude higher than towards Gro3P11, prompting us to genetically explore the physiological functions of PGP activity in mice. Since the developmental delay of PGP-inactivated embryos became manifest before the onset of placenta vascularisation (see Fig. 2a), a primary role of impaired labyrinth formation for embryonic growth retardation appears unlikely. PGP inactivation in these mice was confirmed by analysing phosphatase activity in red blood cell lysates[15] (Supplementary Figs S2, S3 and Supplementary Methods).

Results

Conclusion