A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Science Pub Date : 2024-08-30 DOI:10.1126/science.adj7446

Sara Martin, Simone Scorzoni, Sara Cordone, Alice Mazzagatti, Galina V. Beznoussenko, Amanda L. Gunn, Melody Di Bona, Yonatan Eliezer, Gil Leor, Tal Ben-Yishay, Alessia Loffreda, Valeria Cancila, Maria Chiara Rainone, Marica Rosaria Ippolito, Valentino Martis, Fabio Bedin, Massimiliano Garrè, Laura Pontano Vaites, Paolo Vasapolli, Simona Polo, Dario Parazzoli, Claudio Tripodo, Alexander A. Mironov, Alessandro Cuomo, Uri Ben-David, Samuel F. Bakhoum, Emily M. Hatch, Peter Ly, Stefano Santaguida

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Abstract

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.

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依赖 p62 的流变调节器决定微核灾难和染色体重排

染色体不稳定性（CIN）会产生微核--异常的核外结构，催化癌症中复杂染色体重排的发生。微核的特征是持续的DNA损伤和灾难性的核膜崩解，从而使DNA暴露于细胞质中。我们发现，自噬受体 p62/SQSTM1 可调节微核的稳定性，影响染色体的破碎和重排。从机理上讲，微核靠近线粒体会导致氧化驱动的p62同源异构化，通过触发自噬降解来限制运输所需的内体分选复合体（ESCRT）依赖的微核包膜修复。我们还发现，p62 水平与人类癌细胞系中染色体三分裂的增加以及结直肠肿瘤中 CIN 的增加相关。因此，p62 是微核的调节因子，可作为高 CIN 肿瘤的预后标志物。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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