Pyruvate Facilitates FACT-Mediated γH2AX Loading to Chromatin and Promotes the Radiation Resistance of Glioblastoma.

Abstract

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 γH2AX, 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 γH2AX and subsequently facilitates FACT-mediated chromatin loading of γH2AX, ultimately promoting DNA repair and tumor cell survival. Intriguingly, the supplementation of exogenous pyruvate can also sufficiently enhance FACT-mediated chromatin loading of γH2AX 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 γH2AX loading to chromatin and establishes a critical role of this mechanism in glioblastoma radiation resistance.

• Authors: Siyang Wu, Ruixiu Cao, Bangbao Tao, Ping Wu, Chao Peng, Hong Gao, Ji Liang, Weiwei Yang
• Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (Adv Sci (Weinh)) Vol. 9 Issue 8 Pg. e2104055 (03 2022) ISSN: 2198-3844 [Electronic] Germany
• PMID: 35048565 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.

Chemical References

• Chromatin
• DNA-Binding Proteins
• H2AX protein, human
• High Mobility Group Proteins
• Histones
• SSRP1 protein, human
• Transcriptional Elongation Factors
• Pyruvic Acid
• Pyruvate Kinase

Topics

• Cell Line, Tumor
• Chromatin
• DNA-Binding Proteins (genetics)
• Glioblastoma (genetics, metabolism, pathology)
• High Mobility Group Proteins (genetics)
• Histones
• Humans
• Pyruvate Kinase (genetics, metabolism)
• Pyruvic Acid (metabolism)
• Transcriptional Elongation Factors (genetics)