Genome instability triggers intercellular DNA transfer between human cells.

The mammalian genome is safeguarded within the confines of the interphase nucleus. However, genomic instability can trigger the mislocalization of nuclear DNA to the cytoplasm within micronuclei or as fragmented chromosomes. Beyond activating cell-autonomous signaling programs, whether such cytoplasmic DNA can elicit non-cell-autonomous consequences to nearby cells remains unclear. Here, we show that cytoplasmic DNAs undergo intercellular transfer through contact-dependent, cytoskeleton-based nanotube structures connecting adjacent human cells. Diverse sources of genomic instability-including exposure to mitotic spindle poisons, ionizing radiation, and Cas9-induced chromosome breakage-promote nanotube-mediated DNA transfer in both cancerous and non-cancerous cells. Transferred DNA fragments are stably inherited as functional extrachromosomal genetic elements in the recipient host genome, thereby conferring heritable phenotypic traits to the recipient cell. Our findings uncover a horizontal gene transfer-like mechanism through which direct cell-cell contact can propagate genomic instability and reshape mammalian genomes.