Abstract
The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anti-cancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-γH2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.
Highlights
The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anticancer target
We demonstrate that PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an ataxia-telangiectasia mutated (ATM)-γH2AX-MDC1dependent manner and promotes recruitment of homologous recombination (HR) factors, HR activity, and recovery from IR-induced cell cycle arrest
As RPA32, BRCA1, and RAD51 are essential for functional HR repair, we evaluated the importance of PFKFB3 in HR efficiency employing the DR-GFP assay in U2OS cells[30]
Summary
The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anticancer target. ATM phosphorylates the tail of H2AX at Ser[139] (γH2AX) on the chromatin flanking the DSB, which attracts binding of the mediator of DNA damage checkpoint protein 1 (MDC1), altogether forming a complex and feedback loop resulting in amplification and stabilization of γH2AX. This serves as a platform for recruitment and accumulation of additional DNA repair factors[3,4]. We identify a regulatory role for PFKFB3 enzymatic activity in HR repair and our data suggests that PFKFB3 inhibition by KAN0438757 could be an attractive approach to increase sensitivity to therapeutically induced DNA breaks
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