Selective autophagy targets micronuclei with nuclear envelope defects for complete lysosomal degradation through a process termed chromophagy, which eliminates entrapped chromosomes from the genome, prevents intergenerational transmission of damaged chromosomal material, and suppresses micronucleus-mediated chromosomal instability by competing with the rupture pathway that otherwise leads to chromosome fragmentation and chromothripsis.

Chromosomal instability (CIN) arising from mitotic errors generates pervasive structural and numerical chromosome alterations fueling cancer evolution. Entrapment of missegregated chromosomes within micronuclei exacerbates CIN by fostering repeated rounds of aberrant mitotic segregation and, following micronucleus rupture, promoting catastrophic chromosomal rearrangement processes such as chromothripsis. Whether cellular mechanisms exist to restrain micronucleus-driven CIN has remained unclear. Developing a live-cell chromatin acidification sensor, we tracked micronuclei from genesis through subsequent cell cycles and observed frequent whole-micronucleus capture and acidification via the autophagy pathway. Autophagic targeting is selective for micronuclei with nuclear envelope defects seeded at mitotic exit. Our data indicate that these defects drive progressive loss of chromatin–nuclear envelope tethering, producing a mechanically altered state that is recognised by the autophagic machinery. Autophagy and rupture represent distinct micronuclear fates with opposing genomic consequences. Single-cell sequencing of fate-matched cells demonstrates complete digestion of the chromosomal contents of autophagy-targeted micronuclei, a process we term chromophagy (chromosome-autophagy). By eliminating micronuclei, chromophagy promotes chromosomal loss and arrests the intergenerational transmission of missegregated chromosomal material. This constrains the mutational consequences of micronucleation and suppresses micronucleus-mediated CIN.