期刊
JOURNAL OF CELL BIOLOGY
卷 216, 期 2, 页码 409-424出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201607008
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资金
- China International Science and Technology Cooperation Program [2015DFM30040]
- National Science and Technology Major Project [2015ZX09101009]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12020000]
- Natural Science Foundation of China for Innovation Research Group [81321092]
- Natural Science Foundation of China [81573464, 21377106]
Glycolytic enzymes are known to play pivotal roles in cancer cell survival, yet their molecular mechanisms remain poorly understood. Phosphoglycerate mutase 1 (PGAM1) is an important glycolytic enzyme that coordinates glycolysis, pentose phosphate pathway, and serine biosynthesis in cancer cells. Herein, we report that PGAM1 is required for homologous recombination (HR) repair of DNA double-strand breaks (DSBs) caused by DNA-damaging agents. Mechanistically, PGAM1 facilitates DSB end resection by regulating the stability of CTBP-interacting protein (CtIP). Knockdown of PGAM1 in cancer cells accelerates CtIP degradation through deprivation of the intracellular deoxyribonucleotide triphosphate pool and associated activation of the p53/p73 pathway. Enzymatic inhibition of PGAM1 decreases CtIP protein levels, impairs HR repair, and hence sensitizes BRCA1/2-proficient breast cancer to poly(ADP-ribose) polymerase (PARP) inhibitors. Together, this study identifies a metabolically dependent function of PGAM1 in promoting HR repair and reveals a potential therapeutic opportunity for PGAM1 inhibitors in combination with PARP inhibitors.
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