Open AccessPyruvate Facilitates FACT‐Mediated γ H2AX Loading to Chromatin and Promotes the Radiation Resistance of Glioblastoma
Author(s) -
Wu Siyang,
Cao Ruixiu,
Tao Bangbao,
Wu Ping,
Peng Chao,
Gao Hong,
Liang Ji,
Yang Weiwei
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202104055
Subject(s) - pkm2 , chromatin , dna damage , histone , dna repair , cancer research , microbiology and biotechnology , biology , glycolysis , chemistry , pyruvate kinase , dna , biochemistry , metabolism
DNA repair confers the resistance of tumor cells to DNA‐damaging anticancer therapies, while how reprogrammed metabolism in tumor cells contributes to such process remains poorly understood. Pyruvate kinase M2 isoform (PKM2) catalyzes the conversion of phosphoenolpyruvate to pyruvate and regulates the last rate‐limiting step of glycolysis. Here it is shown that the glycolytic metabolite pyruvate enhances DNA damage repair by facilitating chromatin loading of γ H2AX, thereby promoting the radiation resistance of glioma cells. Mechanistically, PKM2 is phosphorylated at serine (S) 222 upon DNA damage and interacts with FACT complex, a histone chaperone comprising SPT16 and SSRP1 subunit. The pyruvate produced by PKM2 directly binds to SSRP1, which increases the association of FACT complex with γ H2AX and subsequently facilitates FACT‐mediated chromatin loading of γ H2AX, ultimately promoting DNA repair and tumor cell survival. Intriguingly, the supplementation of exogenous pyruvate can also sufficiently enhance FACT‐mediated chromatin loading of γ H2AX and promotes tumor cell survival upon DNA damage. The levels of PKM2 S222 phosphorylation correlate with the malignancy and prognosis of human glioblastoma. The finding demonstrates a novel mechanism by which PKM2‐produced pyruvate promotes DNA repair by regulating γ H2AX loading to chromatin and establishes a critical role of this mechanism in glioblastoma radiation resistance.