Centriole copy number is tightly maintained by the once‐per‐cycle duplication of these organelles. Centrioles constitute the core of centrosomes, which organize the microtubule cytoskeleton and form the poles of the mitotic spindle. Centrosome amplification is frequently observed in tumors, where it promotes aneuploidy and contributes to invasive phenotypes. In non‐transformed cells, centrosome amplification triggers PIDDosome activation as a protective response to inhibit cell proliferation, but how extra centrosomes activate the PIDDosome remains unclear. Using a genome‐wide screen, we identify centriole distal appendages as critical for PIDDosome activation in cells with extra centrosomes. The distal appendage protein ANKRD26 is found to interact with and recruit the PIDDosome component PIDD1 to centriole distal appendages, and this interaction is required for PIDDosome activation following centrosome amplification. Furthermore, a recurrent ANKRD26 mutation found in human tumors disrupts PIDD1 localization and PIDDosome activation in cells with extra centrosomes. Our data support a model in which ANKRD26 initiates a centriole‐derived signal to limit cell proliferation in response to centrosome amplification.

中文翻译：

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ANKRD26 将 PIDD1 募集到中心体远端附件以在中心体扩增后激活 PIDDosome

中心粒拷贝数通过这些细胞器的每周期重复一次来紧密保持。中心粒构成中心体的核心，其组织微管细胞骨架并形成有丝分裂纺锤体的两极。中心体扩增经常在肿瘤中观察到，它促进非整倍性并导致侵袭性表型。在非转化细胞中，中心体扩增触发 PIDDosome 激活作为抑制细胞增殖的保护性反应，但额外的中心体如何激活 PIDDosome 仍不清楚。使用全基因组筛选，我们确定中心粒远端附属物对于具有额外中心体的细胞中的 PIDDosome 激活至关重要。发现远端附肢蛋白 ANKRD26 与 PIDDosome 成分 PIDD1 相互作用并将其募集到中心粒远端附肢，这种相互作用是中心体扩增后 PIDDosome 激活所必需的。此外，在人类肿瘤中发现的复发性 ANKRD26 突变破坏了具有额外中心体的细胞中的 PIDD1 定位和 PIDDosome 激活。我们的数据支持一个模型，其中 ANKRD26 启动中心粒衍生信号以限制细胞增殖以响应中心体扩增。