Many cancer-related proteins are controlled by composite post-translational modifications (PTMs), but prevalent strategies only target one type of modification. Here we describe a designed peptide that controls two types of modifications of the p53 tumor suppressor, based on the discovery of a protein complex that suppresses p53 (suppresome). We found that Morn3, a cancer-testis antigen, recruits different PTM enzymes, such as sirtuin deacetylase and ubiquitin ligase, to confer composite modifications on p53. The molecular functions of Morn3 were validated throughin vivoassays and chemico-biological intervention. A rationally designed Morn3-targeting peptide (Morncide) successfully activated p53 and suppressed tumor growth. These findings shed light on the regulation of protein PTMs and present a strategy for targeting two modifications with one molecule.

中文翻译：

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一种设计的肽靶向具有抗癌活性的两种类型的p53修饰

许多与癌症相关的蛋白质受复合翻译后修饰（PTM）的控制，但流行的策略仅针对一种修饰类型。在这里，我们基于抑制p53（超现实体）的蛋白复合物的发现，描述了一种设计的肽，该肽可控制p53肿瘤抑制子的两种修饰。我们发现，Morn3是一种癌症-睾丸抗原，它募集了不同的PTM酶（如瑟土因脱乙酰基酶和泛素连接酶）来赋予p53复合修饰。Morn3的分子功能已通过体内测定和化学生物学干预得到验证。合理设计的靶向Morn3的肽（Morncide）成功激活了p53，并抑制了肿瘤的生长。