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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 which the resulting pyruvate is converted to lactate at the expense of efficient energy production. This rewired metabolism is likely dictated by the elevated requirements of cancer cells and proliferating cells in general for the production of biomass, including fatty acids, amino acids, and nucleotides (Vander Heiden et al., 2009). For biosynthesis of nucleotides, an essential intermediate is NAD PH, which is produced predominantly by the pentose phosphate pathway (PPP). In this pathway, glucose-6-phosphate is converted into ribose-5-phosphate, the sugar backbone of nucleotides. In line with the elevated requirement for anabolic metabolism, glycolytic enzymes, including those functioning in the PPP, are found to be up-regulated in various cancers (Durany et al., 2000). Within the glycolytic pathway, the phosphoglycerate mutase enzyme (PGAM, also called PGM), catalyzes the conversion of 3-phosphoglycerate (3PG) to 2PG (Fig. 1 A). Two isoforms of PGAM have been reported: PGAM1 and PGAM2. Both isoforms have similar catalytic activity and exist in heteroand homodimers (Mikawa et al., 2014). The substrate of PGAM, 3PG, inhibits the enzymatic activity of the PPP component 6-phosphogluconate dehydrogenase. As a consequence, by converting 3PG into 2PG, PGAM functions to stimulate PPP pathway flux and to ensure biosynthesis. This pivotal role in coordinating glycolysis with biosynthesis makes PGAM an attractive cancer therapeutic target, as its inhibition may interfere with essential needs of cancer cells. Indeed, chemical or genetic inhibition of PGAM1 leads to reduced rates of oxidative PPP, declined biosynthesis, and was shown to inhibit tumor growth in a xenograft tumor model (Hitosugi et al., 2012). The nucleotides that are produced as as a result of PPP flux are required for DNA replication in proliferating cells. DNA replication, especially in cancer cells, is not without hazard. Unscheduled firing of replication origins caused by oncogene activation, as well as increased transcriptional activity leading to collisions between the transcription and replication machineries, may stall replication forks and lead to fork collapse (Hills and Diffley, 2014). In addition to sufficient building blocks, replicating cells require proper DNA repair to safeguard genome stability. Homologous recombination (HR) is critical to mend collapsed replication forks. The initial step in HR involves resection of DNA ends to create stretches of single-stranded DNA (ssDNA). In eukaryotic cells, initiation of DNA end resection is governed by the Mre11–Rad50–Nbs1 complex, in conjunction with the DNA double-strand break end resection factor CTBP-interacting protein (CtIP). The resulting ssDNA is ultimately covered with Rad51 filaments, which govern homology search and pairing of the ssDNA with the intact template DNA. Not only does HR facilitate the repair of collapsed replication forks, but non-replication–associated DNA double-strand breaks can also be repaired with high fidelity using HR, at least when cells are in S–G2. Defective HR, for instance, caused by cancer-associated mutations in BRCA1/BRCA2, gives rise to enhanced sensitivity to agents that perturb DNA replication, including poly (ADP-ribose) polymerase (PARP) inhibitors and DNA cross-linking agents such as cisplatin (Evers et al., 2010). In this issue, Qu et al. describe that inactivation of PGAM1 results in defective DNA repair through HR. Indeed, the researchers observed via SIL AC-based proteomics analyses that PGAM1 depletion is associated with changes in protein abundance that underscored metabolic rewiring as well as with perturbations of the levels of proteins involved in the DNA damage response. Notably, PGAM inactivation induced down-regulation of the HR component CtIP. Further characterization of the phenotypes of PGAM1-depleted HeLa cells showed that PGAM1 depletion leads to enhanced sensitivity to DNA damaging agents, including camptothecin, cisplatin, and the PARP inhibitor olaparib (Qu et al., 2017). The requirement for PGAM1 in HR repair involves its enzymatic activity, as Qu et al. (2017) observed that a small molecule inhibitor of PGAM or introduction of a catalytically inactive PGAM mutant effectively interfered with HR repair of DNA double-strand breaks. In accordance with its role in facilitating DNA end resection, the decreased abundance of CtIP upon PGAM1 depletion prevented DNA end resection as well as subsequent steps in HR, including replication protein A recruitment and Rad51 filament formation at sites of DNA damage. Consequently, Qu et al. Phosphoglycerate mutase 1 (PGAM1) functions in glycolysis. In this issue, Qu et al. (2017. J. Cell Biol. https ://doi .org /10 .1083 /jcb .201607008) show that PGAM1 inactivation leads to nucleotide depletion, which causes defective homologous recombination– mediated DNA repair, suggesting that targeting metabolic enzymes increases cancer cell susceptibility to DNA damaging agents. Shutting down the power supply for DNA repair in cancer cells