Micronuclei-entrapped chromosomes present a unique liability to genomic integrity due to their vulnerability to iterative cycles of complex chromosomal rearrangement which can accelerate cancer karyotype evolution. Although cells possess numerous checkpoints and safeguards that promote faithful chromosome segregation and limit micronucleation and aneuploidy, the extent to which they can mitigate the genome-destabilizing consequences of micronuclei once formed has remained unclear. In this work we describe chromophagy (chromosome-autophagy), a selective autophagy pathway operating in human cells which targets whole micronuclei for degradation.

Live-imaging, single cell sequencing (strand-seq)

Using a live-cell chromatin acidification sensor we tracked micronuclei from genesis through subsequent cell cycles. We find that a significant subset of micronuclei undergo autophagy-mediated lysosomal acidification across a panel of human cell lines. This process entails whole-micronucleus capture within large autophagosomal structures followed by lysosomal fusion and acidification. Micronuclei targeting is selective, and our data support a model in which selectivity is conferred through progressive loss of chromatin–nuclear envelope tethering, producing a mechanically altered state that is selectively recognised by the autophagic machinery. By coupling live cell imaging with haplotype-resolved genomic sequencing of single cells, we observe that this process selectively removes micronucleus-entrapped chromosomes from the genome, thus preventing the transmission of genomic material particularly susceptible to DNA rearrangement to daughter cells

By preventing micronuclei transmission, chromophagy can limit the iterative generation of complex chromosomal alterations over successive cell cycles, thereby arresting the self-propagating dynamics of micronucleus-driven chromosomal instability.