A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements

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, exposing DNA to the cytoplasm and driving a pro-inflammatory, pro-metastatic environment. Here, we identify the autophagic receptor p62/SQSTM1 as a regulator of micronuclei. p62 modulates micronuclear stability, influencing chromosome fragmentation and rearrangements, via exerting local spatial control on peri-micronuclear ESCRT-mediated repair activity. We demonstrate that proximity of micronuclei to mitochondria leads to oxidation-driven homo-oligomerization of p62, which triggers autophagic degradation of ESCRT components, thereby limiting their repair activity. Notably, we find that p62 levels correlate with increased chromothripsis across human cancer cell lines and with increased CIN in colorectal tumors. Thus, our study identifies p62 as a novel regulator of micronuclei and indicates that it may serve as a prognostic marker of tumors with high CIN.