Journal Club

A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements

Science

30 Aug 2024

Vol 385, Issue 6

A high rate of chromosome mis-segregation, known as chromosomal instability, is a pervasive feature of tumors. Mis-segregated chromosomes can be encapsulated into micronuclei, abnormal nuclear structures that fuel the acquisition of complex chromosomal rearrangements upon envelope collapse. Two groups of investigators now provide mechanistic insights into micronuclei collapse and the consequences of this process for cancer (see the Perspective by Maddaluno and Settembre). Martin et al. report that mitochondria-derived reactive oxygen species (ROS) oxidize the autophagic protein p62, enhancing its autophagic activity toward components of the repair machinery and thus increasing micronuclear collapse. Elevated p62 levels are associated with increased chromosomal rearrangements in cancer cells and in high–chromosomal instability tumors, pointing to p62 as a potential prognostic marker for such tumors. Di Bona et al. found that ROS interfere with a membrane repair protein called CHMP7, which normally helps to maintain the integrity of the nuclear envelope. ROS cause CHMP7 to cluster and bind with another protein, LEMD2, leading to the breakdown of micronuclei. This collapse contributes to genetic abnormalities and inflammation, linking oxidative damage to cancer’s aggressive behavior. —Stella M. Hurtley