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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：核仁胚胎瘤介导泌乳杂环素释放和核毒性癌细胞的核破坏

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摘要

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 mu m 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：核仁和自噬在维持核完整性方面的作用是较差的。此外，常规化学疗法后癌细胞核破坏机制尚不清楚。为了试图阐明这些问题，我们研究了用依托泊苷（ETO）处理的畸形癌PA1细胞，聚焦在核仁上。治疗后，大多数细胞进入G2骤停，显示持续的DNA损伤并激活P53，衰老和显微育药标记。含有纤维素（FIB）和损伤的RDNA的2-5μm米米核苷类聚集体（NOA），用泛素，Pampk和LC3-II分致大致伴随着异粒素片段，当旋转过度胰岛素片段时。在特异性抑制剂施用后的微观计数揭示了FIB-NOA的形成取决于偶联蛋白蛋白酶体系的缺乏偶联，偶联与功能性自噬。相反，伴随的泌乳杂物蛋白释放超过其频率的泌乳杂项，通过自噬助焊剂的脱节来青睐。潜在的幸存者在稀有线索期间在细胞质中释放NOA，而终调片段的出口通常耗尽H3K9ME3，有或不包括NOA，通过核壳的核仁突起和缺陷发生。 LC3-II的焦点在接受RDNA转录停止的核仁中积累。作为异圆锥素碎片的起源，在核核祝异象蛋白壳中发现未划分的DNA合成和圆形DNA，以及Alu元素的活化和转回，用NOAs中的45s rdNA分致大致化。该数据表明基本核仁功能与自噬调节在维持通过反转横向的不活动的核仁相关结构域的完整性的协调。

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