Dysfunction of the ribosome manifests during cellular senescence and contributes to tissue aging, functional decline, and development of aging-related disorders in ways that have remained enigmatic. Here, we conducted a comprehensive CRISPR-based loss-of-function (LOF) screen of ribosome-associated genes (RAGs) in human mesenchymal progenitor cells (hMPCs). Through this approach, we identified ribosomal protein L22 (RPL22) as the foremost RAG whose deficiency mitigates the effects of cellular senescence. Consequently, absence of RPL22 delays hMPCs from becoming senescent, while an excess of RPL22 accelerates the senescence process. Mechanistically, we found in senescent hMPCs, RPL22 accumulates within the nucleolus. This accumulation triggers a cascade of events, including heterochromatin decompaction with concomitant degradation of key heterochromatin proteins, specifically heterochromatin protein 1γ (HP1γ) and heterochromatin protein KRAB-associated protein 1 (KAP1). Subsequently, RPL22-dependent breakdown of heterochromatin stimulates the transcription of ribosomal RNAs (rRNAs), triggering cellular senescence. In summary, our findings unveil a novel role for nucleolar RPL22 as a destabilizer of heterochromatin and a driver of cellular senescence, shedding new light on the intricate mechanisms underlying the aging process.

中文翻译：

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CRISPR 筛选发现核仁 RPL22 是异染色质不稳定因子和衰老驱动因素


核糖体功能障碍在细胞衰老过程中表现出来，并导致组织衰老、功能下降和衰老相关疾病的发展，其方式仍然是个谜。在这里，我们对人间充质祖细胞 （hMPC） 中的核糖体相关基因 （RAG） 进行了基于 CRISPR 的全面功能丧失 （LOF） 筛选。通过这种方法，我们确定核糖体蛋白 L22 （RPL22） 是最重要的 RAG，其缺陷减轻了细胞衰老的影响。因此，缺乏 RPL22 会延迟 hMPC 衰老，而过量的 RPL22 会加速衰老过程。从机制上讲，我们发现在衰老的 hMPC 中，RPL22 在核仁内积累。这种积累会触发一连串事件，包括异染色质压缩以及关键异染色质蛋白的降解，特别是异染色质蛋白 1γ （HP1γ） 和异染色质蛋白 KRAB 相关蛋白 1 （KAP1）。随后，异染色质的 RPL22 依赖性分解刺激核糖体 RNA （rRNA） 的转录，触发细胞衰老。总之，我们的研究结果揭示了核仁 RPL22 作为异染色质不稳定剂和细胞衰老驱动因素的新作用，为衰老过程的复杂机制提供了新的视角。