GTP signaling links metabolism, DNA repair, and responses to genotoxic stress
GTP signaling links metabolism, DNA repair, and responses to genotoxic stress
ABSTRACT 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 G 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.
Gy?rffy Bal¨￠zs、Speth Jennifer、Kari Wilder-Romans、Lin Angelica、Yang John、Yang Annabel、Walker Natalie、Peterson Erik R.、Werner Christian K.、Obrien Alexandra M.、Elaimy Ameer L.、Zhao Shuang G.、Al-Holou Wajd N、Morgan Meredith A.、Lawrence Theodore S.、Lyssiotis Costas A.、Peters-Golden Marc、Korimerla Navyateja、Kothari Ayesha U.、Zhang Shuqun、Umemura Yoshie、Yao Yangyang、Shah Yatrik M.、Jacobson Janna、Zhao Zitong、Palavalasa Sravya、Zhou Weihua、Wahl Daniel R.、Solanki Sumeet、Li Jing、Scott Andrew J.、Xu Jie、Sarkaria Jann N.、Ferris Sean P.、Liang Jessica
Department of Bioinformatics and 2(nd) Department of Pediatrics, Semmelweis University TTK Cancer Biomarker Research Group, Institute of EnzymologyDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Radiation Oncology, University of MichiganDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Human Oncology, University of Wisconsin MadisonDepartment of Neurosurgery, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Molecular and Integrative Physiology and Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of MichiganDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Oncology, the Second Affiliated Hospital of Xi?ˉan Jiaotong UniversityDepartment of Neurology, University of MichiganDepartment of Oncology, the First Affiliated Hospital of Nanchang UniversityDepartment of Molecular & Integrative Physiology, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Radiation Oncology, University of Michigan||Department of Oncology, the Second Affiliated Hospital of Xi?ˉan Jiaotong UniversityDepartment of Radiation Oncology, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Radiation Oncology, University of MichiganDepartment of Molecular & Integrative Physiology, University of MichiganCell Signaling Technology, Inc.Department of Radiation Oncology, University of MichiganDepartment of Radiation Oncology, University of MichiganMayo ClinicDepartment of Pathology, Division of Neuropathology, University of MichiganDepartment of Radiation Oncology, University of Michigan
基础医学分子生物学肿瘤学
GTP signaling pathwayRac1 pathwayAbl interactor 1(Abi-1)Phosphorylation and DephosphorylationNHEJ DNA RepairRadioresistanceRadioprotection
Gy?rffy Bal¨￠zs,Speth Jennifer,Kari Wilder-Romans,Lin Angelica,Yang John,Yang Annabel,Walker Natalie,Peterson Erik R.,Werner Christian K.,Obrien Alexandra M.,Elaimy Ameer L.,Zhao Shuang G.,Al-Holou Wajd N,Morgan Meredith A.,Lawrence Theodore S.,Lyssiotis Costas A.,Peters-Golden Marc,Korimerla Navyateja,Kothari Ayesha U.,Zhang Shuqun,Umemura Yoshie,Yao Yangyang,Shah Yatrik M.,Jacobson Janna,Zhao Zitong,Palavalasa Sravya,Zhou Weihua,Wahl Daniel R.,Solanki Sumeet,Li Jing,Scott Andrew J.,Xu Jie,Sarkaria Jann N.,Ferris Sean P.,Liang Jessica.GTP signaling links metabolism, DNA repair, and responses to genotoxic stress[EB/OL].(2025-03-28)[2025-05-14].https://www.biorxiv.org/content/10.1101/2023.04.12.536297.点此复制
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