Fumarase (FH) and DNA-PK regulate each other in a feedback manner to drive DNA DSB repair.

  • Major finding: Fumarase (FH) and DNA-PK regulate each other in a feedback manner to drive DNA DSB repair.

  • Mechanism: FH-generated fumarate inhibits KDM2B-mediated histone H3K36me2 demethylation to promote NHEJ repair.

  • Impact: Metabolic enzymes can respond to extracellular stimuli by regulating nonmetabolic cellular activities.

DNA double-strand breaks (DSB), one of the most toxic forms of DNA damage, are primarily repaired in eukaryotic cells by one of two mechanisms, homologous recombination (HR) or non–homologous end-joining (NHEJ), and faulty DSB repair in normal cells is a major driver of cancer. It has previously been shown that decreased fumarase (FH), which metabolizes fumarate, impairs DNA damage repair and promotes tumorigenesis; however, the mechanisms underlying FH-dependent DNA repair are unclear. Jiang and colleagues found that exposure to ionizing radiation (IR), the major exogenous cause of DSBs, resulted in increased binding of FH to histones, in particular the histone variant H2A.Z. Chromatin immunoprecipitation analyses revealed that H2A.Z promoted the recruitment of FH to DSBs, which was necessary for accumulation of the Ku70–Ku80 heterodimer, a central component of the DNA-dependent protein kinase (DNA-PK) holoenzyme that mediates NHEJ. IR induced DNA-PK–mediated phosphorylation of FH at Thr236, resulting in FH and DNA-PK complex binding specifically at DSBs and stimulation of NHEJ-dependent, but not HR-dependent, repair. Furthermore, FH-driven local generation of fumarate at DSBs inhibited lysine (K)-specific demethylase 2B (KDM2B)–mediated demethylation of dimethylated histone H3 Lys36 (H3K36me2), leading to increased association of Ku70 at DSBs, enhanced NHEJ, and increased cell survival in cell lines representing multiple tumor types. Taken together, these results delineate a feedback mechanism of reciprocal regulation between FH and DNA-PK that modulates histone methylation and promotes NHEJ-driven repair of DSBs and survival of cancer cells. In addition, these findings provide evidence of the critical roles of chromatin-localized FH and its metabolic product fumarate in cellular functions independent of metabolism.

Jiang Y, Qian X, Shen J, Wang, Y, Li X, Liu R, et al. Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nat Cell Biol 2015;17:1158–68.

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