Skip NavigationSkip to Content
Return Return to Search Results

Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition

  1. Author:
    Li, Haojian
    Furusawa, Takashi
    Cavero, Renzo
    Xiao, Yunjie
    Chari,Raj
    Wu,Xiaolin
    Sun, David
    Hartmann, Oliver
    Dhall, Anjali
    Holewinski,Ronald
    Andresson,Thorkell
    Karim,Baktiar
    Villamor-Payà, Marina
    Gallardo, Devorah
    Day, Chi-Ping
    Pal, Lipika R
    Nair, Nishanth Ulhas
    Ruppin, Eytan
    Aladjem, Mirit I
    Pommier, Yves
    Diefenbacher, Markus E
    Lim, Jung Mi
    Levine, Rodney L
    Stracker, Travis H
    Weyemi, Urbain

  2. Author Address

    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., Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USA., Genome Modification Core, Laboratory Animal Sciences Program, Frederick, MD, USA., NCI Genomics Technology Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research/ Frederick, Maryland, USA., 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., Protein Characterization Laboratory/Cancer Research Technology Program/Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Molecular Histopathology Laboratory/ Cancer Research Technology Program/Frederick National Laboratory for Cancer Research/ Frederick, Maryland, USA., Radiation Oncology Branch/CCR/NCI, USA., Laboratory Animal Sciences Program, Leidos Biomedical Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Cancer Data Science Lab/ Center for Cancer Research/National Cancer Institute/National Institutes of Health, Bethesda, MD, 20892, USA., Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, Bethesda, MD, USA., Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USA. Electronic address: urbain.weyemi@nih.gov.,
    1. Year: 2025
    2. Date: Jan 19
    3. Epub Date: 2025 01 19
  2. Journal: Redox Biology
    1. 80
    2. Pages: 103503
  4. Type of Article: Article
  5. Article Number: 103503
  1. 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. Published by Elsevier B.V.

    See More

  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.1016/j.redox.2025.103503
  3. PMID: 39854937
  4. PMCID: 39854937
  5. PII : S2213-2317(25)00016-3

Library Notes

  1. Fiscal Year: FY2024-2025
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel