Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition
Year: 2025
Type: article
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.
Source: Redox Biology
Authors: 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
Institutions: National Institutes of Health, National Cancer Institute, Center for Cancer Research, The University of Texas at Austin, Frederick National Laboratory for Cancer Research, Helmholtz Munich, German Center for Lung Research, Leidos Biomedical Research Inc. (United States), National Heart, Lung, and Blood Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,310
Awards: G4689185066, G6252953675
OpenAlex ID: W4406569965