Small but strong: Mutational and functional landscapes of micronuclei in cancer genomes

Abstract Micronuclei, small spatially‐separated, nucleus‐like structures, are a common feature of human cancer cells. There are considerable heterogeneities in the sources, structures and genetic activities of micronuclei. Accumulating evidence suggests that micronuclei and main nuclei represent separate entities with respect to DNA replication, DNA damage sensing and repairing capacity because micronuclei are not monitored by the same checkpoints nor covered by the same nuclear envelope as the main nuclei. Thus, micronuclei are spatially restricted “mutation factories.” Several large‐scale DNA sequencing and bioinformatics studies over the last few years have revealed that most micronuclei display a mutational signature of chromothripsis immediately after their generation and the underlying molecular mechanisms have been dissected extensively. Clonal expansion of the micronucleated cells is context‐dependent and is associated with chromothripsis and several other mutational signatures including extrachromosomal circular DNA, kataegis and chromoanasynthesis. These results suggest what was once thought to be merely a passive indicator of chromosomal instability is now being recognized as a strong mutator phenotype that may drive intratumoral genetic heterogeneity. Herein, we revisit the actionable determinants that contribute to the bursts of mutagenesis in micronuclei and present the growing number of evidence which suggests that micronuclei have distinct short‐ and long‐term mutational and functional effects to cancer genomes. We also pose challenges for studying the long‐term effects of micronucleation in the upcoming years.