Pyruvate Facilitates FACT-Mediated γH2AX Loading to Chromatin and Promotes the Radiation Resistance of Glioblastoma.
Pyruvate Facilitates FACT-Mediated γH2AX Loading to Chromatin and Promotes the Radiation Resistance of Glioblastoma.
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丙酮酸促进了事实介导的γH2AX负载，从而促进染色质，并促进胶质母细胞瘤的辐射耐药性。
DOI：
10.1002/advs.202104055
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Yang W
中科院分区：
文献类型：
--
作者：
Wu S;Cao R;Tao B;Wu P;Peng C;Gao H;Liang J;Yang W
DNA修复赋予肿瘤细胞对DNA损伤性抗癌疗法的抵抗力，而肿瘤细胞中重新编程的代谢如何促进这一过程仍知之甚少。丙酮酸激酶 M2 同工型 (PKM2) 催化磷酸烯醇丙酮酸转化为丙酮酸，并调节糖酵解的最后限速步骤。这里表明，糖酵解代谢物丙酮酸通过促进γH2AX的染色质负载来增强DNA损伤修复，从而促进神经胶质瘤细胞的辐射抵抗力。从机制上讲，PKM2 在 DNA 损伤后在丝氨酸 (S) 222 处被磷酸化，并与 FACT 复合物（一种包含 SPT16 和 SSRP1 亚基的组蛋白伴侣）相互作用。 PKM2 产生的丙酮酸直接与 SSRP1 结合，从而增加 FACT 复合物与 γH2AX 的结合，随后促进 FACT 介导的 γH2AX 染色质负载，最终促进 DNA 修复和肿瘤细胞存活。有趣的是，补充外源性丙酮酸还可以充分增强 FACT 介导的 γH2AX 染色质负载，并促进 DNA 损伤后肿瘤细胞的存活。 PKM2 S222磷酸化水平与人胶质母细胞瘤的恶性程度和预后相关。这一发现证明了 PKM2 产生的丙酮酸通过调节 γH2AX 负载到染色质来促进 DNA 修复的新机制，并确立了该机制在胶质母细胞瘤抗辐射性中的关键作用。 DNA 修复赋予肿瘤细胞对 DNA 损伤性抗癌疗法的抵抗力，而肿瘤细胞中重新编程的代谢如何促进 DNA 修复过程仍知之甚少。吴等人。在此证明，糖酵解代谢物丙酮酸促进 FACT 复合物介导的 γH2AX 负载到染色质并增强受损 DNA 的修复，从而促进胶质母细胞瘤的辐射抵抗力。
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. DNA repair confers the resistance of tumor cells to DNA‐damaging anticancer therapies, while how reprogrammed metabolism in tumor cells contributes to the process of DNA repair remains poorly understood. Wu et al. demonstrate here that the glycolytic metabolite pyruvate facilitates the FACT complex‐mediated γH2AX loading to chromatin and enhances repair of damaged DNA, thereby promoting radiation resistance of glioblastoma.
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影响因子：
13.8
作者：
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