Human skin tolerates a surprisingly high burden of oncogenic lesions. Although adult epidermis can suppress the expansion of individual mutant clones, the mechanisms behind tolerance to oncogene activation across broader regions of tissue are unclear. Here, we uncover a dynamic translational mechanism that coordinates oncogenic HRAS-induced hyperproliferation with loss of progenitor self-renewal to restrain aberrant growth and tumorigenesis. We identify translation initiator eIF2B5 as a central co-regulator of HRAS proliferation and cell fate choice. By coupling in vivo ribosome profiling with genetic screening, we provide direct evidence that oncogene-induced loss of progenitor self-renewal is driven by eIF2B5-mediated translation of ubiquitination genes. Ubiquitin ligase FBXO32 specifically inhibits epidermal renewal without affecting overall proliferation, thus restraining HRAS-driven tumorigenesis while maintaining normal tissue growth. Thus, oncogene-driven translation is not necessarily inherently tumor promoting but instead can manage widespread oncogenic stress by steering progenitor fate to prolong normal tissue growth.

人类皮肤能够承受令人惊讶的高致癌损伤负担。尽管成人表皮可以抑制单个突变克隆的扩张，但更广泛的组织区域对癌基因激活的耐受性背后的机制尚不清楚。在这里，我们发现了一种动态翻译机制，该机制协调致癌 HRAS 诱导的过度增殖与祖细胞自我更新的丧失，以抑制异常生长和肿瘤发生。我们将翻译起始子 eIF2B5 确定为 HRAS 增殖和细胞命运选择的核心共同调节因子。通过将体内核糖体分析与遗传筛选相结合，我们提供了直接证据，证明癌基因诱导的祖细胞自我更新丧失是由 eIF2B5 介导的泛素化基因翻译驱动的。泛素连接酶 FBXO32 特异性抑制表皮更新而不影响整体增殖，从而抑制 HRAS 驱动的肿瘤发生，同时维持正常组织生长。因此，癌基因驱动的翻译不一定本质上促进肿瘤，而是可以通过控制祖细胞命运来延长正常组织的生长来管理广泛的致癌应激。