ESCRT-III accumulates in micronuclei with ruptured nuclear envelopes
ESCRT-III accumulates in micronuclei with ruptured nuclear envelopes
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DOI：
10.1101/476630
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发表时间：
2018-12
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影响因子：
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通讯作者：
Jessica Willan;A. Cleasby;N. Flores-Rodriguez;Flavia Stefani;C. Rinaldo;Alessandra Pisciottani;E. Gran
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文献类型：
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作者：
Jessica Willan;A. Cleasby;N. Flores-Rodriguez;Flavia Stefani;C. Rinaldo;Alessandra Pisciottani;E. Gran
微核代表细胞试图划分 DNA，以维持受到有丝分裂错误和基因毒性事件威胁的基因组完整性。微核显示异常的核膜崩溃，产生受损的 DNA 并促进复杂的基因组改变。然而，破裂的微核也提供了刺激抗肿瘤免疫的胞质 DNA 库，揭示了微核对肿瘤进展影响的复杂性。 ESCRT-III 复合体确保有丝分裂晚期核膜 (NE) 重新密封以及间期 NE 修复。因此，ESCRT-III 活性可能对于维持核膜包围的其他基因组结构的完整性至关重要。核膜上的 ESCRT-III 活性由亚基 CHMP7 协调。我们证明 CHMP7 和 ESCRT-III 可以防止与微核形成相关的基因组不稳定性。 ESCRT-III 活性的丧失会增加间期细胞中核膜破裂的微核数量。令人惊讶的是，ESCRT-III 保留在无心微核处，表明 ESCRT-III 无法修复这些结构。 CHMP7 表达的耗尽消除了破裂微核处的 ESCRT-III 积累，并消除了含有胞质 DNA 传感器的受损 DNA 的微核群体。因此，ESCRT-III 活性似乎以二分方式防止基因组不稳定的后果。膜修复活性可防止包膜薄弱的 MN 的发生；相反，微核处的异常膜重塑会产生稳定状态的胞质 DNA 池，这可能有助于维持癌细胞中的促炎途径。
Micronuclei represent the cellular attempt to compartmentalize DNA to maintain genomic integrity threatened by mitotic errors and genotoxic events. Micronuclei show aberrant nuclear envelopes that collapse, generating damaged DNA and promoting complex genome alterations. However, ruptured micronuclei also provide a pool of cytosolic DNA that stimulates anti-tumour immunity, revealing the complexity of micronuclei impact on tumour progression. The ESCRT-III complex ensures nuclear envelope (NE) resealing during late mitosis and NE repair in interphase. Therefore, ESCRT-III activity maybe crucial for maintaining the integrity of other genomic structures enclosed by a nuclear envelope. ESCRT-III activity at the nuclear envelope is coordinated by the subunit CHMP7. We show that CHMP7 and ESCRT-III protects against the genomic instability associated with micronuclei formation. Loss of ESCRT-III activity increases the population of micronuclei with ruptured nuclear envelopes, in interphase cells. Surprisingly, ESCRT-III is retained at acentric micronuclei suggesting that ESCRT-III cannot repair these structures. Depletion of CHMP7 expression removes ESCRT-III accumulations at ruptured micronuclei, and removes the population of micronuclei with damaged DNA also containing a sensor for cytosolic DNA. Thus, ESCRT-III activity appears to protect from the consequence of genomic instability in a dichotomous fashion. Membrane repair activity prevents the occurrence of MN with weak envelopes; conversely, aberrant membrane remodelling at micronuclei generates a steady state pool of cytosolic DNA that may contribute to sustaining pro-inflammatory pathways in cancer cells.