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首页> 外文期刊>Cell discovery. >UHRF1 is required for basal stem cell proliferation in response to airway injury
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UHRF1 is required for basal stem cell proliferation in response to airway injury

机译：UHRF1是基底干细胞对气道损伤的反应所必需的

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Cellular senescence is a cell fate characterized by an irreversible cell cycle arrest, but the molecular mechanism underlying this senescence hallmark remains poorly understood. Through an unbiased search for novel senescence regulators in airway basal cells, we discovered that the epigenetic regulator ubiquitin-like with PHD and ring finger domain-containing protein 1 (UHRF1) is critical for regulating cell cycle progression. Upon injury, basal cells in the mouse airway rapidly induce the expression of UHRF1 in order to stimulate stem cell proliferation and tissue repair. Targeted depletion of Uhrf1 specifically in airway basal cells causes a profound defect in cell cycle progression. Consistently, cultured primary human basal cells lacking UHRF1 do not exhibit cell death or differentiation phenotypes but undergo a spontaneous program of senescence. Mechanistically, UHRF1 loss induces G1 cell cycle arrest by abrogating DNA replication factory formation as evidenced by loss of proliferating cell nuclear antigen (PCNA) puncta and an inability to enter the first cell cycle. This proliferation defect is partially mediated by the p15 pathway. Overall, our study provides the first evidence of an indispensable role of UHRF1 in somatic stem cells proliferation during the process of airway regeneration.
机译：细胞衰老是一种以不可逆的细胞周期停滞为特征的细胞命运，但对这一衰老标志的分子机制仍知之甚少。通过在气道基底细胞中无偏见地寻找新的衰老调节因子，我们发现具有PHD和含无名指结构域的蛋白1（UHRF1）的表观遗传调节因子泛素对于调节细胞周期进程至关重要。受伤后，小鼠气道中的基础细胞会迅速诱导UHRF1的表达，从而刺激干细胞增殖和组织修复。 Uhrf1的有针对性的耗竭特别是在气道基底细胞中引起细胞周期进程的严重缺陷。一致地，缺乏UHRF1的培养的人类原代基础细胞不表现出细胞死亡或分化表型，而是经历自然的衰老程序。从机制上讲，UHRF1的丧失通过废除DNA复制工厂的形成而诱导G1细胞周期停滞，如增殖细胞核抗原（PCNA）点状细胞的丢失以及无法进入第一个细胞周期所证明的。该增殖缺陷部分由p15途径介导。总体而言，我们的研究提供了UHRF1在气道再生过程中在体干细胞增殖中不可或缺的作用的第一个证据。

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