Redox Biology (Mar 2025)
Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition
- Haojian Li,
- Takashi Furusawa,
- Renzo Cavero,
- Yunjie Xiao,
- Raj Chari,
- Xiaolin Wu,
- David Sun,
- Oliver Hartmann,
- Anjali Dhall,
- Ronald Holewinski,
- Thorkell Andresson,
- Baktiar Karim,
- Marina Villamor-Payà,
- Devorah Gallardo,
- Chi-Ping Day,
- Lipika R. Pal,
- Nishanth Ulhas Nair,
- Eytan Ruppin,
- Mirit I. Aladjem,
- Yves Pommier,
- Markus E. Diefenbacher,
- Jung Mi Lim,
- Rodney L. Levine,
- Travis H. Stracker,
- Urbain Weyemi
Affiliations
- Haojian Li
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USA; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA
- Takashi Furusawa
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USA
- Renzo Cavero
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USA
- Yunjie Xiao
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USA
- Raj Chari
- Genome Modification Core, Laboratory Animal Sciences Program, Frederick, MD, USA
- Xiaolin Wu
- NCI Genomics Technology Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research/ Frederick, Maryland, USA
- David Sun
- NCI Genomics Technology Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research/ Frederick, Maryland, USA
- Oliver Hartmann
- Comprehensive Pneumology Center (CPC)/Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL/CPC-M), Munich, Germany
- Anjali Dhall
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USA
- Ronald Holewinski
- Protein Characterization Laboratory/Cancer Research Technology Program/Frederick National Laboratory for Cancer Research, Frederick, MD, USA
- Thorkell Andresson
- Protein Characterization Laboratory/Cancer Research Technology Program/Frederick National Laboratory for Cancer Research, Frederick, MD, USA
- Baktiar Karim
- Molecular Histopathology Laboratory/ Cancer Research Technology Program/Frederick National Laboratory for Cancer Research/ Frederick, Maryland, USA
- Marina Villamor-Payà
- Radiation Oncology Branch/CCR/NCI, USA
- Devorah Gallardo
- Laboratory Animal Sciences Program, Leidos Biomedical Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Chi-Ping Day
- Cancer Data Science Lab/ Center for Cancer Research/National Cancer Institute/National Institutes of Health, Bethesda, MD, 20892, USA
- Lipika R. Pal
- Cancer Data Science Lab/ Center for Cancer Research/National Cancer Institute/National Institutes of Health, Bethesda, MD, 20892, USA
- Nishanth Ulhas Nair
- Cancer Data Science Lab/ Center for Cancer Research/National Cancer Institute/National Institutes of Health, Bethesda, MD, 20892, USA
- Eytan Ruppin
- Cancer Data Science Lab/ Center for Cancer Research/National Cancer Institute/National Institutes of Health, Bethesda, MD, 20892, USA
- Mirit I. Aladjem
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USA
- Yves Pommier
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USA
- Markus E. Diefenbacher
- Comprehensive Pneumology Center (CPC)/Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL/CPC-M), Munich, Germany
- Jung Mi Lim
- Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
- Rodney L. Levine
- Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, Bethesda, MD, USA
- Travis H. Stracker
- Radiation Oncology Branch/CCR/NCI, USA
- Urbain Weyemi
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USA; Corresponding author. Developmental Therapeutics Branch National Cancer Institute, National Institutes of Health 37 Convent Drive, Bethesda, MD, 20892, USA.
- Journal volume & issue
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Vol. 80
p. 103503
Abstract
Metabolic pathways fuel tumor progression and resistance to stress conditions including chemotherapeutic drugs, such as DNA damage response (DDR) inhibitors. Yet, significant gaps persist in how metabolic pathways confer resistance to DDR inhibition in cancer cells. Here, we employed a metabolism-focused CRISPR knockout screen and identified genetic vulnerabilities to DDR inhibitors. We unveiled Peroxiredoxin 1 (PRDX1) as a synthetic lethality partner with Ataxia Telangiectasia Mutated (ATM) kinase. Tumor cells depleted of PRDX1 displayed heightened sensitivity to ATM inhibition in vitro and in mice in a manner dependent on p53 status. Mechanistically, we discovered that the ribosomal protein RPL32 undergoes redox modification on active cysteine residues 91 and 96 upon ATM inhibition, promoting p53 stability and altered cell fitness. Our findings reveal a new pathway whereby RPL32 senses stress and induces p53 activation impairing tumor cell survival.
