American Association for Cancer Research
cd-23-0437_supplementary_data_1_suppsd1.xlsx (2.05 MB)

Supplementary Data 1 from GTP Signaling Links Metabolism, DNA Repair, and Responses to Genotoxic Stress

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posted on 2024-01-12, 08:21 authored by 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, Balázs Győrffy, 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

Supplementary Data 1 shows the original data of phosphoproteomic assay in Figure 2.


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National Institute of Neurological Disorders and Stroke (NINDS)

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Damon Runyon Cancer Research Foundation (DRCRF)

Sontag Foundation (The Sontag Foundation)

National Heart, Lung, and Blood Institute (NHLBI)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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A. Alfred Taubman Medical Research Institute (Taubman Institute)



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, which 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 nonhomologous 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 nonmalignant 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. A newly described GTP-dependent signaling axis is an unexpected link between nucleotide metabolism and DNA repair. Disrupting this pathway can overcome cancer resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues.This article is featured in Selected Articles from This Issue, p. 5

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