GTP 信号传导将新陈代谢、DNA 修复和对基因毒性应激的反应联系起来。
GTP signaling links metabolism, DNA repair, and responses to genotoxic stress.
发表日期：2023 Oct 30
作者：
Weihua Zhou, Zitong Zhao, Angelica Lin, John Z Yang, Jie Xu, Kari Wilder-Romans, Annabel Yang, Jing Li, Sumeet Solanki, Jennifer M Speth, Natalie Walker, Andrew J Scott, Lu Wang, Bo Wen, Anthony Andren, Li Zhang, Ayesha U Kothari, Yangyang Yao, Erik R Peterson, Navyateja Korimerla, Christian K Werner, Alexander Ullrich, Jessica Liang, Janna Jacobson, Sravya Palavalasa, Alexandra M O'Brien, Ameer L Elaimy, Sean P Ferris, Shuang G Zhao, Jann N Sarkaria, Balazs Gyorffy, Shuqun Zhang, Wajd N Al-Holou, Yoshie Umemura, Meredith A Morgan, Theodore S Lawrence, Costas A Lyssiotis, Marc Peters-Golden, Yatrik M Shah, Daniel R Wahl
来源：
Brain Structure & Function
摘要：
细胞代谢如何调节 DNA 修复尚不完全清楚。在这里，我们定义了一个 GTP 介导的信号级联，它将新陈代谢与 DNA 修复联系起来，并具有重要的治疗意义。 GTP（而非其他核苷酸）调节 Rac1（一种鸟嘌呤核苷酸结合蛋白）的活性，促进蛋白磷酸酶 5 (PP5) 对 Abl 相互作用子 1 (Abi-1) 上丝氨酸 323 的去磷酸化。去磷酸化的 Abi-1 是一种以前未知的激活 DNA 修复的蛋白质，可促进非同源末端连接。在胶质母细胞瘤患者和小鼠模型中，Rac1 和去磷酸化的 Abi-1 介导 DNA 修复和对标准护理基因毒性治疗的抵抗。 GTP-Rac1-PP5-Abi-1 信号轴不仅限于脑癌，因为补充 GTP 可以促进非恶性细胞中的 DNA 修复和 Abi-1-S323 去磷酸化，并保护小鼠组织免受基因毒性损伤。 GTP 这种独立于脱氧核苷酸池调节 DNA 修复的意想不到的能力对于正常生理学和癌症治疗具有重要意义。
How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a guanine nucleotide-binding protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.