当前位置: X-MOL 学术Redox Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition
Redox Biology ( IF 10.7 ) Pub Date : 2025-01-19 , DOI: 10.1016/j.redox.2025.103503
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 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.

中文翻译:


代谢依赖性映射确定过氧化物还原蛋白 1 是 ATM 抑制耐药的驱动因素



代谢途径会促进肿瘤进展和对应激条件的抵抗力,包括化疗药物,如 DNA 损伤反应 (DDR) 抑制剂。然而,在代谢途径如何赋予癌细胞对 DDR 抑制的耐药性方面仍然存在重大差距。在这里,我们采用了以代谢为中心的 CRISPR 敲除筛选,并确定了 DDR 抑制剂的遗传脆弱性。我们揭示了过氧化物还原蛋白 1 (PRDX1) 作为共济失调毛细血管扩张突变 (ATM) 激酶的合成致死伴侣。PRDX1 耗尽的肿瘤细胞在体外和小鼠中以依赖于 p53 状态的方式表现出对 ATM 抑制的更高敏感性。从机制上讲,我们发现核糖体蛋白 RPL32 在 ATM 抑制后对活性半胱氨酸残基 91 和 96 进行氧化还原修饰,促进 p53 稳定性和细胞适应性改变。我们的研究结果揭示了一种新的途径,RPL32 通过该途径感知压力并诱导 p53 激活,从而损害肿瘤细胞存活。
更新日期:2025-01-19
down
wechat
bug