Phosphoglycerate Mutase 1 Activates DNA Damage Repair via Regulation of WIP1 Activity

Shigeo Ohba; Tor-Christian Aase Johannessen; Kamalakar Chatla; Xiaodong Yang; Russell O Pieper; Joydeep Mukherjee

doi:10.1016/j.celrep.2020.03.082

Phosphoglycerate Mutase 1 Activates DNA Damage Repair via Regulation of WIP1 Activity

Cell Rep. 2020 Apr 14;31(2):107518. doi: 10.1016/j.celrep.2020.03.082.

Authors

Shigeo Ohba¹, Tor-Christian Aase Johannessen², Kamalakar Chatla³, Xiaodong Yang³, Russell O Pieper³, Joydeep Mukherjee⁴

Affiliations

¹ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurosurgery, Fujita Health University, Toyoake, Aichi, Japan.
² Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen, Norway.
³ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: joydeep.mukherjee@ucsf.edu.

PMID: 32294440
DOI: 10.1016/j.celrep.2020.03.082

Abstract

The metabolic enzyme phosphoglycerate mutase 1 (PGAM1) is overexpressed in several types of cancer, suggesting an additional function beyond its established role in the glycolytic pathway. We here report that PGAM1 is overexpressed in gliomas where it increases the efficiency of the DNA damage response (DDR) pathway by cytoplasmic binding of WIP1 phosphatase, thereby preventing WIP1 nuclear translocation and subsequent dephosphorylation of the ATM signaling pathway. Silencing of PGAM1 expression in glioma cells consequently decreases formation of γ-H2AX foci, increases apoptosis, and decreases clonogenicity following irradiation (IR) and temozolomide (TMZ) treatment. Furthermore, mice intracranially implanted with PGAM1-knockdown cells have significantly improved survival after treatment with IR and TMZ. These effects are counteracted by exogenous expression of two kinase-dead PGAM1 mutants, H186R and Y92F, indicating an important non-enzymatic function of PGAM1. Our findings identify PGAM1 as a potential therapeutic target in gliomas.

Keywords: DNA damage repair; PGAM1; WIP1; glioma; irradiation; temozolomide.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / genetics
DNA Damage / physiology
DNA Repair / genetics
DNA Repair / physiology*
Female
Humans
Male
Mice
Phosphoglycerate Mutase / genetics
Phosphoglycerate Mutase / metabolism*
Protein Phosphatase 2C / genetics
Protein Phosphatase 2C / metabolism*

Substances

PPM1D protein, human
Protein Phosphatase 2C
Phosphoglycerate Mutase
phosphoglycerate mutase 1, human