TY - JOUR
T1 - Phosphoglycerate Mutase 1 Activates DNA Damage Repair via Regulation of WIP1 Activity
AU - Ohba, Shigeo
AU - Johannessen, Tor Christian Aase
AU - Chatla, Kamalakar
AU - Yang, Xiaodong
AU - Pieper, Russell O.
AU - Mukherjee, Joydeep
N1 - Funding Information:
We thank Wendy See and Ilona Garner for their diligent proofreading of this paper. This work was supported in part by National Institutes of Health grant NS105087-02 (R.O.P.) and The Kristian Gerhard Jebsen Foundation (to T.-C.A.J.).
PY - 2020/4/14
Y1 - 2020/4/14
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2020.03.082
DO - 10.1016/j.celrep.2020.03.082
M3 - Article
C2 - 32294440
AN - SCOPUS:85083016205
VL - 31
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 2
M1 - 107518
ER -