Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition
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-fo...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-03-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725000163 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Haojian Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1c7e9e211cd047cebe94db05a8c2e5a8 |
| institution | DOAJ |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-1c7e9e211cd047cebe94db05a8c2e5a82025-08-20T03:11:54ZengElsevierRedox Biology2213-23172025-03-018010350310.1016/j.redox.2025.103503Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibitionHaojian Li0Takashi Furusawa1Renzo Cavero2Yunjie Xiao3Raj Chari4Xiaolin Wu5David Sun6Oliver Hartmann7Anjali Dhall8Ronald Holewinski9Thorkell Andresson10Baktiar Karim11Marina Villamor-Payà12Devorah Gallardo13Chi-Ping Day14Lipika R. Pal15Nishanth Ulhas Nair16Eytan Ruppin17Mirit I. Aladjem18Yves Pommier19Markus E. Diefenbacher20Jung Mi Lim21Rodney L. Levine22Travis H. Stracker23Urbain Weyemi24Developmental 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, USADevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USADevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USADevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USAGenome Modification Core, Laboratory Animal Sciences Program, Frederick, MD, USANCI Genomics Technology Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research/ Frederick, Maryland, USANCI Genomics Technology Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research/ Frederick, Maryland, USAComprehensive Pneumology Center (CPC)/Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL/CPC-M), Munich, GermanyDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USAProtein Characterization Laboratory/Cancer Research Technology Program/Frederick National Laboratory for Cancer Research, Frederick, MD, USAProtein Characterization Laboratory/Cancer Research Technology Program/Frederick National Laboratory for Cancer Research, Frederick, MD, USAMolecular Histopathology Laboratory/ Cancer Research Technology Program/Frederick National Laboratory for Cancer Research/ Frederick, Maryland, USARadiation Oncology Branch/CCR/NCI, USALaboratory Animal Sciences Program, Leidos Biomedical Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USACancer Data Science Lab/ Center for Cancer Research/National Cancer Institute/National Institutes of Health, Bethesda, MD, 20892, USACancer Data Science Lab/ Center for Cancer Research/National Cancer Institute/National Institutes of Health, Bethesda, MD, 20892, USACancer Data Science Lab/ Center for Cancer Research/National Cancer Institute/National Institutes of Health, Bethesda, MD, 20892, USACancer Data Science Lab/ Center for Cancer Research/National Cancer Institute/National Institutes of Health, Bethesda, MD, 20892, USADevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USADevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USAComprehensive Pneumology Center (CPC)/Institute of Lung Health and Immunity (LHI), Helmholtz Munich, Member of the German Center for Lung Research (DZL/CPC-M), Munich, GermanyLaboratory of Biochemistry, National Heart, Lung, and Blood Institute, Bethesda, MD, USALaboratory of Biochemistry, National Heart, Lung, and Blood Institute, Bethesda, MD, USARadiation Oncology Branch/CCR/NCI, USADevelopmental 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.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.http://www.sciencedirect.com/science/article/pii/S2213231725000163ATM kinasePeroxiredoxin 1Disulfide stressp53 activationRPL32 redox modification |
| spellingShingle | 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 Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition Redox Biology ATM kinase Peroxiredoxin 1 Disulfide stress p53 activation RPL32 redox modification |
| title | Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition |
| title_full | Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition |
| title_fullStr | Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition |
| title_full_unstemmed | Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition |
| title_short | Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition |
| title_sort | metabolic dependency mapping identifies peroxiredoxin 1 as a driver of resistance to atm inhibition |
| topic | ATM kinase Peroxiredoxin 1 Disulfide stress p53 activation RPL32 redox modification |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725000163 |
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