Phosphoglycerate mutase 1 regulates dNTP pool and promotes homologous recombination repair in cancer cells
نویسندگان
چکیده
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.
منابع مشابه
Correction: Phosphoglycerate mutase 1 regulates dNTP pool and promotes homologous recombination repair in cancer cells
After publication, the authors realized that an antibody and siRNAs used in the paper were incorrect. Specifically, the antibody reported as Cdh1 in Fig. 5 E was instead an antibody against CDH1 (Cadherin). In addition, the three siRNAs in Fig. 5 E reported as siCdh1#1, siCdh1#2, and siCdh1#3 were also inadvertently synthesized against CDH1 (Cadherin). Upon discovering the error, the authors ge...
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295 The Rockefeller University Press $30.00 J. Cell Biol. Vol. 216 No. 2 295–297 https://doi.org/10.1083/jcb.201701026 Deregulated metabolism is a hallmark of cancer. Most normal differentiated cells only display low glycolysis rates, of which the resulting pyruvate is used to produce ATP through aerobic phosphorylation. In contrast, tumor cells have highly increased rates of glycolysis, after ...
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