PDF(Pubmed)
Abstract：
The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.
摘要：
DNA损伤反应对于维持基因组完整性至关重要，并且通常在癌症发展中被破坏。PPM1D（蛋白磷酸酶Mg2/Mn2依赖性1D）是反应的主要负调节因子；在几种人类癌症中发现了PPM1D的功能获得突变和扩增，使其成为相关的药理靶标。这里,我们使用CRISPR/Cas9筛选来鉴定PPM1D的合成致死依赖性，揭示超氧化物歧化酶-1（SOD1）作为PPM1D突变细胞的潜在靶标。我们揭示了一种失调的氧化还原景观，其特征是PPM1D突变细胞中活性氧水平升高和对氧化应激的反应受损。总之,我们的结果证明SOD1在PPM1D突变的白血病细胞的存活中发挥了作用,并突出了针对PPM1D突变的癌症的新的潜在治疗策略.
