Redox biology · 2025
Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition.
СтатьяResearch Support, N.I.H., IntramuralПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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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
Аннотация
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.