Phosphoglycerate mutase 1 regulates dNTP pool and promotes homologous recombination repair in cancer cells

Jia Qu; Wenyi Sun; Jie Zhong; Hao Lv; Mingrui Zhu; Jun Xu; Nan Jin; Zuoquan Xie; Minjia Tan; Shu-Hai Lin; Meiyu Geng; Jian Ding; Min Huang

doi:10.1083/jcb.201607008

Phosphoglycerate mutase 1 regulates dNTP pool and promotes homologous recombination repair in cancer cells

J Cell Biol. 2017 Feb;216(2):409-424. doi: 10.1083/jcb.201607008. Epub 2017 Jan 25.

Authors

Jia Qu^{1

2}, Wenyi Sun², Jie Zhong³, Hao Lv², Mingrui Zhu², Jun Xu², Nan Jin², Zuoquan Xie², Minjia Tan², Shu-Hai Lin³, Meiyu Geng², Jian Ding^{4

2}, Min Huang⁵

Affiliations

¹ State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ 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.
⁴ State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China [email protected] [email protected].
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [email protected] [email protected].

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.

MeSH terms

A549 Cells
Animals
Apoptosis
BRCA1 Protein / metabolism
BRCA2 Protein / metabolism
Carrier Proteins / metabolism
Cell Cycle
Cell Proliferation
Cell Survival
DNA Breaks, Double-Stranded*
Deoxyribonucleotides / metabolism*
Dose-Response Relationship, Drug
Endodeoxyribonucleases
Female
Gene Expression Regulation, Neoplastic
HeLa Cells
Humans
Mass Spectrometry
Mice, Inbred BALB C
Mice, Nude
Neoplasms / drug therapy
Neoplasms / enzymology*
Neoplasms / genetics
Neoplasms / pathology
Nuclear Proteins / metabolism
Phosphoglycerate Mutase / antagonists & inhibitors
Phosphoglycerate Mutase / genetics
Phosphoglycerate Mutase / metabolism*
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Poly(ADP-ribose) Polymerases / metabolism
Protein Stability
Proteomics / methods
RNA Interference
Recombinational DNA Repair*
Time Factors
Transfection
Tumor Burden
Tumor Protein p73 / metabolism
Tumor Suppressor Protein p53 / metabolism
Xenograft Model Antitumor Assays

Substances

BRCA1 Protein
BRCA1 protein, human
BRCA2 Protein
BRCA2 protein, human
Carrier Proteins
Deoxyribonucleotides
Nuclear Proteins
Poly(ADP-ribose) Polymerase Inhibitors
TP53 protein, human
TP73 protein, human
Tumor Protein p73
Tumor Suppressor Protein p53
Poly(ADP-ribose) Polymerases
Endodeoxyribonucleases
RBBP8 protein, human
Phosphoglycerate Mutase
phosphoglycerate mutase 1, human