single-cell RNA sequencing data of HeLa, DLD-1 and recipient HeLa cells
The mammalian genome is safeguarded within the confines of the interphase nucleus. However, genomic instability can trigger the mis-localization of nuclear DNA to the cytoplasm within micronuclei or as fragmented chromatin. 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 – provoke nanotube-mediated DNA transfer in both cancer 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.