Cellular response to aneuploidy and formation of micronuclei. Histone H3.3, an Aurora B target, is differentially phosphorylated at Ser31 on laggards (center) and misaligned chromosomes (right) in metaphase and anaphase cells, which is necessary for p53 accumulation in the nucleus of aneuploid daughter cells. Chromosomes that do not segregate with the main chromosome mass are enclosed by nuclear envelope (NE) components in a differential manner, which can lead to defective deposition of NPCs and other non-core components to the newly formed NE. The integrity of NE on micronuclei derived from misaligned chromosomes is currently unknown. Micronuclei (mNE) with a defective NE can rupture and expose their DNA to the cytosolic environment, leading to extensive DNA damage. p53 promotes the degradation of TREX1 endonuclease via the proteasome, facilitating the activation of cGAS-STING and consequent innate immune response due to the accumulation of cytosolic dsDNA from ruptured micronuclei, which are potential hubs for chromothripsis. Aneuploidy and micronuclei in non-transformed cells cause a p53-dependent reduction in cell proliferation and viability. Alterations in the p53 status may alternatively increase fitness and proliferative potential in certain contexts, potentiating tumor evolution and metastasis.