Figure 1.

PGAM1 inhibition blocks repair of DNA breaks through HR. (A) PGAM1 functions in glycolysis by converting 3PG into 2PG. A parallel branch of the glycolysis pathway—the PPP—is used to create biomass, including nucleotides. Under normal circumstances, DNA double-strand breaks are repaired through HR. A critical first step in HR is Mre11–Rad50–Nbs1 (MRN)/CtIP–mediated DNA end resection. (B) When PGAM1 is inactivated, its substrate 3PG accumulates and inhibits 6-phosphogluconate dehydrogenase (6PGD) in the PPP, leading to nucleotide pool depletion. The resulting replication stress response leads to p53/p73-dependent up-regulation of p21 and subsequent activation of the APC/C-Cdh1 E3 ubiquitin ligase. This leads to ubiquitylation and degradation of CtIP, which precludes efficient HR DNA repair.