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However, the precise molecular mechanisms coordinating these processes remain unclear. This study reveals a previously unrecognized role of the platelet isoform of phosphofructokinase-1 (PFKP) in homologous recombination (HR) repair. Our investigations demonstrated that ataxia-telangiectasia mutated (ATM) kinase phosphorylates PFKP at residue T278, promoting its transition from tetramers to dimers in response to ionizing radiation (IR) and high glucose (HG) stimulation. The nuclear localized dimeric PFKP recruits casein kinase 2 (CK2), which subsequently phosphorylates RAD51 at residue T13, thereby enhancing the RAD51-BRCA2 interaction and HR efficiency. Clinically, PFKP exhibits significant nuclear accumulation in diabetes-associated malignancies. Importantly, simultaneous targeting of glycolysis and the HR pathway increases tumor sensitivity to radiotherapy. These findings elucidate the pivotal role of PFKP as a metabolic molecular switch that balances glycolysis and DDR, offering new perspectives for the development of metabolically targeted anticancer strategies.<\/jats:p>","DOI":"10.1093\/nar\/gkag336","type":"journal-article","created":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T11:37:40Z","timestamp":1775302660000},"source":"Crossref","is-referenced-by-count":2,"title":["ATM promotes PFKP nuclear translocation to balance glycolysis and homologous recombination repair"],"prefix":"10.1093","volume":"54","author":[{"given":"Haoyun","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center , Beijing 100191 ,","place":["China"]},{"name":"Gastroenterology Center, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital , Fuzhou, Fujian Province 350001 ,","place":["China"]},{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Peking University International Hospital , Beijing 102206 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7022-659X","authenticated-orcid":false,"given":"Zhanzhan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center , Beijing 100191 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of Biochemistry and Molecular Biology, School of life Sciences, Peking University , Beijing 100871 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center , Beijing 100191 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weibin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine, School of Basic Medical Sciences, Peking University International Cancer Institute, Institute of Advanced Clinical Medicine, State Key Laboratory of Molecular Oncology, Peking University Health Science Center , Beijing 100191 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