Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation. The ribosomal proteins (RPs), comprising the structural parts of the ribosome, are essential for ribosome assembly and function. In addition to their canonical ribosomal functions, multiple RPs have extra-ribosomal functions including activation of p53-dependent or p53-independent pathways in response to stress, resulting in cell cycle arrest and apoptosis. Defects in ribosome biogenesis, translation, and the functions of individual RPs, including mutations in RPs have been linked to a diverse range of human congenital disorders termed ribosomopathies. Ribosomopathies are characterized by tissue-specific phenotypic abnormalities and higher cancer risk later in life. Recent discoveries of somatic mutations in RPs in multiple tumor types reinforce the connections between ribosomal defects and cancer. In this article, we review the most recent advances in understanding the molecular consequences of RP mutations and ribosomal defects in ribosomopathies and cancer. We particularly discuss the molecular basis of the transition from hypo- to hyper-proliferation in ribosomopathies with elevated cancer risk, a paradox termed “Dameshek’s riddle.” Furthermore, we review the current treatments for ribosomopathies and prospective therapies targeting ribosomal defects. We also highlight recent advances in ribosome stress-based cancer therapeutics. Importantly, insights into the mechanisms of resistance to therapies targeting ribosome biogenesis bring new perspectives into the molecular basis of cancer susceptibility in ribosomopathies and new clinical implications for cancer therapy.

核糖体生物合成和蛋白质合成是细胞生长和增殖的基本限速步骤。构成核糖体结构部分的核糖体蛋白 (RP) 对核糖体的组装和功能至关重要。除了其典型的核糖体功能外，多个 RP 还具有核糖体外功能，包括响应压力激活 p53 依赖性或 p53 非依赖性途径，导致细胞周期停滞和细胞凋亡。核糖体生物发生、翻译和单个 RP 功能的缺陷，包括 RP 的突变，与称为核糖体病的多种人类先天性疾病有关。核糖体病的特点是组织特异性表型异常和生命后期的癌症风险较高。最近在多种肿瘤类型中发现的 RP 体细胞突变加强了核糖体缺陷与癌症之间的联系。在本文中，我们回顾了在了解核糖体病和癌​​症中 RP 突变和核糖体缺陷的分子后果方面的最新进展。我们特别讨论了癌症风险升高的核糖体病从低增殖到高增殖转变的分子基础，这个悖论被称为“Dameshek 之谜”。此外，我们回顾了核糖体病的当前治疗方法和针对核糖体缺陷的前瞻性治疗方法。我们还强调了基于核糖体压力的癌症疗法的最新进展。重要的，