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首页> 外文期刊>Nucleus >Nucleolar aggresomes mediate release of pericentric heterochromatin and nuclear destruction of genotoxically treated cancer cells
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Nucleolar aggresomes mediate release of pericentric heterochromatin and nuclear destruction of genotoxically treated cancer cells

机译：核仁聚集体介导周缘异染色质的释放和经基因毒性处理的癌细胞的核破坏

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The role of the nucleolus and autophagy in maintenance of nuclear integrity is poorly understood. In addition, the mechanisms of nuclear destruction in cancer cells senesced after conventional chemotherapy are unclear. In an attempt to elucidate these issues, we studied teratocarcinoma PA1 cells treated with Etoposide (ETO), focusing on the nucleolus. Following treatment, most cells enter G2 arrest, display persistent DNA damage and activate p53, senescence, and macroautophagy markers. 2–5?μm sized nucleolar aggresomes (NoA) containing fibrillarin (FIB) and damaged rDNA, colocalized with ubiquitin, pAMPK, and LC3-II emerge, accompanied by heterochromatin fragments, when translocated perinuclearly. Microscopic counts following application of specific inhibitors revealed that formation of FIB-NoA is dependent on deficiency of the ubiquitin proteasome system coupled to functional autophagy. In contrast, the accompanying NoAs release of pericentric heterochromatin, which exceeds their frequency, is favored by debilitation of autophagic flux. Potential survivors release NoA in the cytoplasm during rare mitoses, while exit of pericentric fragments often depleted of H3K9Me3, with or without encompassing by NoA, occurs through the nucleolar protrusions and defects of the nuclear envelope. Foci of LC3-II are accumulated in the nucleoli undergoing cessation of rDNA transcription. As an origin of heterochromatin fragmentation, the unscheduled DNA synthesis and circular DNAs were found in the perinucleolar heterochromatin shell, along with activation and retrotransposition of ALU elements, colocalized with 45S rDNA in NoAs. The data indicate coordination of the basic nucleolar function with autophagy regulation in maintenance of the integrity of the nucleolus associated domains secured by inactivity of retrotransposons.
机译：人们对核仁和自噬在维持核完整性中的作用了解甚少。此外，常规化疗后引起的癌细胞核破坏的机制尚不清楚。为了阐明这些问题，我们研究了依托泊苷（ETO）处理的畸胎瘤PA1细胞，重点研究了核仁。治疗后，大多数细胞进入G2阻滞状态，表现出持续的DNA损伤并激活p53，衰老和巨自噬标记物。含有原纤维蛋白（FIB）和受损的rDNA的2–5μm大小的核仁聚集体（NoA）与泛素，pAMPK和LC3-II共同定位，并在核周移位时伴随着异染色质片段。应用特定抑制剂后的显微计数显示，FIB-NoA的形成取决于泛素蛋白酶体系统与功能自噬结合的缺乏。相反，自噬通量的衰弱有利于伴随的NoAs释放的超中心异染色质超过其频率。潜在的幸存者在稀有的有丝分裂过程中在细胞质中释放NoA，而经常被H3K9Me3耗尽的周向片段的退出（通过或不通过NoA进行包围）通过核仁突起和核被膜缺陷发生。 LC3-II的病灶积累在核仁中，而核仁经历了rDNA转录的停止。作为异染色质片段化的起源，在周核异染色质外壳中发现了计划外的DNA合成和环状DNA，以及与NoS中45S rDNA共定位的ALU元素的活化和逆转座。数据表明基本的核仁功能与自噬调节在维持逆转录转座子失活所确保的核仁相关结构域完整性方面的协调。

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