Importin α Characterizes a micronuclear environment associated with genomic instability in human cancer cells

Micronuclei (MN) are membrane-enclosed chromatin bodies and hallmarks of genome instability. Here, we show that importin α, a key nuclear transport factor, accumulates prominently in a distinct subset of MN in cultured human cancer cells. The selective localization is associated with defective Ran-dependent nucleocytoplasmic recycling of importin α1 within MN, consistent with impaired nuclear export. This was supported by live-cell photobleaching analyses, which revealed markedly reduced mobility of importin α1 between MN and the cytoplasm. Notably, importin α1 was enriched in euchromatin regions within MN and colocalized with chromatin-associated molecules, defining a chromatin-linked micronuclear context. In contrast, DNA repair and DNA-sensing molecules such as RAD51, RPA2, and cGAS showed mutually exclusive localization with importin α1 in MN, indicating that MN comprise functionally distinct internal states. Consistent with the functional heterogeneity, single MN genome-wide analyses further linked distinct MN states to different patterns of genome instability in cancer cells. Together, these findings identify importin α as a molecular marker of a transport-restricted, chromatin-associated MN subset. This framework offers new insights into MN heterogeneity and genome instability during cancer progression.