Research team Nina Gustafsson
Metabolic regulation of genome stability
Recent investigations have identified involvement of different metabolic enzymes and metabolites in the response to DNA damage in order to maintain the genome integrity of the cancer cell; the glycolytic enzyme PKM2 regulates DNA repair, the oncometabolite D-2-hydroxyglutarate inhibits DNA repair enzymes, chemosensitization occurs in isocitrate dehydrogenase (IDH1/2) mutant gliomas and the enzymatic activity of fumarase and its metabolite are required for the cellular DNA damage response upon induction of double-strand breaks Thus, uncovering new links between cancer metabolism and genome stability, which is the aim of our research, holds great promise in development of novel anti-cancer strategies. More specifically, we are characterizing the role of metabolism in DNA repair and replication and whether metabolic enzymes have functions in response to DNA damaging therapies in cancer.
Characterize the role of the glycolytic enzyme PFKFB3 in DNA repair and replication in cancer
PFKFB3 is a metabolic enzyme that catalyzes the synthesis and degradation of Fructose 2,6-bisphosphate, the main allosteric modulator of the first rate-limiting step in the glycolysis. It is a transcriptional target of several oncogenic transcription factors and a recognized anti-cancer target. We identified PFKFB3 as being essential for cancer cells to repair lethal DNA double-strand breaks upon radiotherapy. PFKFB3 is a key regulator of homologous recombination (HR) repair and its nuclear localization and activity is central for localization of RAD51 to these lesions (Gustafsson et al. Nat Commun 9, 3872, 2018). Our goal is to fully characterize the mechanistic role of PFKFB3 and associated enzymes in DNA repair and replication in cancer using state-of-the-art molecular biology techniques and extend our findings to patient material through clinical collaborations.
Our research is generously supported by grants from:
- The Swedish Childhood Cancer Foundation (Barncancerfonden)
- Dr Åke Olsson's Foundation
- Magnus Bergvalls Foundation
- Åke Wibergs Foundation
- Sagen's Foundation