GTP Signaling Links Metabolism, DNA Repair, and Responses to Genotoxic Stress-Reference-Cited by-同舟云学术

GTP Signaling Links Metabolism, DNA Repair, and Responses to Genotoxic Stress

Published:2023-10-30 Issue:1 Volume:14 Page:158-175
ISSN:2159-8274
Container-title:Cancer Discovery
language:en
Short-container-title:

Author:

Zhou Weihua¹^ORCID,Zhao Zitong¹²^ORCID,Lin Angelica¹^ORCID,Yang John Z.¹^ORCID,Xu Jie¹^ORCID,Wilder-Romans Kari¹^ORCID,Yang Annabel¹^ORCID,Li Jing³^ORCID,Solanki Sumeet⁴^ORCID,Speth Jennifer M.⁵^ORCID,Walker Natalie⁵^ORCID,Scott Andrew J.¹⁶^ORCID,Wang Lu⁷^ORCID,Wen Bo⁷^ORCID,Andren Anthony⁴^ORCID,Zhang Li⁴^ORCID,Kothari Ayesha U.¹^ORCID,Yao Yangyang¹⁸^ORCID,Peterson Erik R.¹^ORCID,Korimerla Navyateja¹^ORCID,Werner Christian K.¹^ORCID,Ullrich Alexander¹^ORCID,Liang Jessica¹^ORCID,Jacobson Janna¹^ORCID,Palavalasa Sravya¹^ORCID,O’Brien Alexandra M.¹^ORCID,Elaimy Ameer L.¹^ORCID,Ferris Sean P.⁹^ORCID,Zhao Shuang G.¹⁰^ORCID,Sarkaria Jann N.¹¹^ORCID,Győrffy Balázs¹²¹³^ORCID,Zhang Shuqun²^ORCID,Al-Holou Wajd N.¹⁴^ORCID,Umemura Yoshie¹⁵^ORCID,Morgan Meredith A.¹^ORCID,Lawrence Theodore S.¹^ORCID,Lyssiotis Costas A.⁴⁶¹⁶¹⁷^ORCID,Peters-Golden Marc⁵^ORCID,Shah Yatrik M.⁴⁶^ORCID,Wahl Daniel R.¹⁶^ORCID

Affiliation:

1. 1Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

2. 2Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, PR China.

3. 3Cell Signaling Technology, Inc., Danvers, Massachusetts.

4. 4Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.

5. 5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.

6. 6Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.

7. 7Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan.

8. 8Department of Oncology, the First Affiliated Hospital of Nanchang University, Nanchang, PR China.

9. 9Department of Pathology, Division of Neuropathology, University of Michigan, Ann Arbor, Michigan.

10. 10Department of Human Oncology, University of Wisconsin Madison, Massachusetts.

11. 11Mayo Clinic, Rochester, Minnesota.

12. 12Department of Bioinformatics, Semmelweis University, Budapest, Hungary.

13. 13TTK Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary.

14. 14Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan.

15. 15Department of Neurology, University of Michigan, Ann Arbor, Michigan.

16. 16Department of Molecular and Integrative Physiology, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.

17. 17Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.

Abstract

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 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. SIGNIFICANCE: 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

Funder

National Cancer Institute

National Institute of Neurological Disorders and Stroke

Damon Runyon Cancer Research Foundation

Sontag Foundation

National Heart, Lung, and Blood Institute

National Institute of Diabetes and Digestive and Kidney Diseases

A. Alfred Taubman Medical Research Institute

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology