title: Phosphoglycerate mutase 1 regulates dNTP pool and promotes homologous recombination repair in cancer cells.
abstract: 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.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Qu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Lv
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Mingrui
authors.initials: M
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zuoquan
authors.identifier: 0000-0002-1613-3321
authors.initials: Z
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Minjia
authors.initials: M
authors.lastname: Tan
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Shu-Hai
authors.identifier: 0000-0002-4782-5320
authors.initials: SH
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China mhuang@simm.ac.cn jding@simm.ac.cn.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China mhuang@simm.ac.cn jding@simm.ac.cn.
authors.forename: Min
authors.identifier: 0000-0001-6735-1612
authors.initials: M
authors.lastname: Huang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D017209:Apoptosis; D019313:BRCA1 Protein / Q000378:metabolism; D024682:BRCA2 Protein / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D003854:Deoxyribonucleotides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004706:Endodeoxyribonucleases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D013058:Mass Spectrometry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010736:Phosphoglycerate Mutase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D055550:Protein Stability; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D059767:Recombinational DNA Repair; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D000072160:Tumor Protein p73 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D002352:Carrier Proteins; D003854:Deoxyribonucleotides; D009687:Nuclear Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C495901:TP53 protein, human; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human; D010736:Phosphoglycerate Mutase; C000611372:phosphoglycerate mutase 1, human