代谢依赖性图谱确定过氧化物酶1是对ATM抑制产生抗性的驱动因素。
Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition.
作者信息
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
机构信息
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.
出版信息
Redox Biol. 2025 Mar;80:103503. doi: 10.1016/j.redox.2025.103503. Epub 2025 Jan 19.
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.
代谢途径为肿瘤进展提供能量，并赋予肿瘤对包括化疗药物（如DNA损伤反应（DDR）抑制剂）在内的应激条件的抗性。然而，关于代谢途径如何赋予癌细胞对DDR抑制的抗性，仍然存在重大差距。在此，我们进行了一项以代谢为重点的CRISPR基因敲除筛选，并确定了对DDR抑制剂的基因脆弱性。我们发现过氧化物酶1（PRDX1）是与共济失调毛细血管扩张突变（ATM）激酶的合成致死伴侣。在体外和小鼠体内，缺失PRDX1的肿瘤细胞对ATM抑制表现出更高的敏感性，其方式依赖于p53状态。从机制上讲，我们发现核糖体蛋白RPL32在ATM抑制后，其活性半胱氨酸残基91和96会发生氧化还原修饰，从而促进p53的稳定性并改变细胞适应性。我们的研究结果揭示了一条新的途径，即RPL32感知应激并诱导p53激活，从而损害肿瘤细胞的存活。
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