Chromosomal instability (CIN) generates micronuclei—aberrant extranuclear structures that catalyze the acquisition of complex chromosomal rearrangements present in cancer. Micronuclei are characterized by persistent DNA damage and catastrophic nuclear envelope collapse, which exposes DNA to the cytoplasm. We found that the autophagic receptor p62/SQSTM1 modulates micronuclear stability, influencing chromosome fragmentation and rearrangements. Mechanistically, proximity of micronuclei to mitochondria led to oxidation-driven homo-oligomerization of p62, limiting endosomal sorting complex required for transport (ESCRT)–dependent micronuclear envelope repair by triggering autophagic degradation. We also found that p62 levels correlate with increased chromothripsis across human cancer cell lines and with increased CIN in colorectal tumors. Thus, p62 acts as a regulator of micronuclei and may serve as a prognostic marker for tumors with high CIN.

中文翻译：

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p62 依赖性变阻器决定微核灾难和染色体重排


染色体不稳定性 （CIN） 产生微核——异常的核外结构，催化癌症中存在的复杂染色体重排的获得。微核的特征是持续的 DNA 损伤和灾难性的核膜崩溃，这会使 DNA 暴露在细胞质中。我们发现自噬受体 p62/SQSTM1 调节微核稳定性，影响染色体碎裂和重排。从机制上讲，微核接近线粒体导致 p62 的氧化驱动的同寡聚化，通过触发自噬降解限制了运输所需的内体分选复合物 （ESCRT） 依赖性的微核包膜修复。我们还发现 p62 水平与人类癌细胞系中染色体裂解的增加以及结直肠肿瘤中 CIN 的增加相关。因此，p62 充当微核的调节因子，可作为高 CIN 肿瘤的预后标志物。