Perturbations in ribosome biogenesis have been associated with cancer. Such aberrations activate p53 through the RPL5/RPL11/5S rRNA complex-mediated inhibition of HDM2. Studies using animal models have suggested that this signaling pathway might constitute an important anticancer barrier. To gain a deeper insight into this issue in humans, here we analyze somatic mutations in RPL5 and RPL11 coding regions, reported in The Cancer Genome Atlas and International Cancer Genome Consortium databases. Using a combined computational and statistical approach, complemented by a range of biochemical and functional analyses in human cancer cell models, we demonstrate the existence of several mechanisms by which RPL5 mutations may impair wild-type p53 upregulation and ribosome biogenesis. Unexpectedly, the same approach provides only modest evidence for a similar role of RPL11, suggesting that RPL5 represents a preferred target during human tumorigenesis in cancers with wild-type p53. Furthermore, we find that several functional cancer-associated RPL5 somatic mutations occur as rare germline variants in general population. Our results shed light on the so-far enigmatic role of cancer-associated mutations in genes encoding ribosomal proteins, with implications for our understanding of the tumor suppressive role of the RPL5/RPL11/5S rRNA complex in human malignancies.

核糖体生物发生的扰动与癌症有关。这种异常通过 RPL5/RPL11/5S rRNA 复合物介导的 HDM2 抑制激活 p53。使用动物模型的研究表明，这种信号通路可能构成重要的抗癌屏障。为了更深入地了解人类的这个问题，我们分析了RPL5和RPL11编码区的体细胞突变，这些突变在癌症基因组图谱和国际癌症基因组联盟数据库中报告。使用组合的计算和统计方法，辅以人类癌细胞模型中的一系列生化和功能分析，我们证明了RPL5存在几种机制突变可能会损害野生型 p53 上调和核糖体生物合成。出乎意料的是，相同的方法仅为RPL11的类似作用提供了适度的证据，表明RPL5代表了野生型 p53 癌症中人类肿瘤发生过程中的首选靶标。此外，我们发现几种功能性癌症相关的RPL5体细胞突变在一般人群中作为罕见的种系变异发生。我们的研究结果揭示了迄今为止癌症相关突变在编码核糖体蛋白的基因中的神秘作用，这对我们理解 RPL5/RPL11/5S rRNA 复合物在人类恶性肿瘤中的肿瘤抑制作用具有重要意义。