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

• DOI: 10.1083/jcb.201607008
• Publication Date: 2017-01-25T15:10:14Z
• Authors: 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
• Keywords: Phosphoglycerate mutase

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 cells. Herein, we report PGAM1 required for homologous recombination (HR) repair of DNA double-strand breaks (DSBs) caused by DNA-damaging agents. Mechanistically, facilitates DSB end resection regulating the stability CTBP-interacting protein (CtIP). Knockdown cells accelerates CtIP degradation through deprivation intracellular deoxyribonucleotide triphosphate pool associated activation p53/p73 pathway. Enzymatic inhibition decreases levels, impairs HR repair, hence sensitizes BRCA1/2-proficient breast poly(ADP-ribose) polymerase (PARP) inhibitors. Together, this study identifies a metabolically dependent function promoting reveals potential therapeutic opportunity inhibitors combination with PARP