Human Cells Can Pass Damaged DNA Directly to Neighbors Through Nanotube Bridges

For decades, the mammalian genome was considered strictly cell-autonomous — confined within the nucleus of a single cell and isolated from its neighbors. This landmark study published in Cell overturns that assumption by demonstrating that genomic instability can trigger the physical transfer of nuclear DNA fragments from one human cell into the genome of an adjacent cell, via microscopic nanotube connections. The implications are profound: genome damage is not just a private cellular crisis — it can propagate laterally across a tissue.

The research team at UT Southwestern used hTERT-immortalized human retinal pigment epithelial (RPE-1) cells and renal proximal tubule epithelial cells (RPTECs), along with HeLa cancer cells, to study this phenomenon. Genomic instability was induced through multiple orthogonal methods: treatment with CENP-E and Mps1 inhibitors to cause mitotic segregation errors, prolonged nocodazole arrest followed by release, Mad2 depletion to accelerate mitotic exit, CRISPR-Cas9-induced chromosomal double-strand breaks on chromosome 3p, and 2 Gy ionizing radiation. In all cases, cytoplasmic DNA — visualized with SiR-DNA dye and fluorescently tagged histone H2B — was observed transiting through nanotube structures connecting adjacent cells.

To definitively prove intercellular transfer (rather than cytoplasmic contamination or bridges), the team co-cultured cells expressing H2B-GFP with cells expressing H2B-mCherry. Successful DNA transfer produced recipient cells with mismatched H2B labeling between nucleus and cytoplasm — a signature that was quantified across 2,867 cells from three independent experiments. Between 1.1% and 3.9% of micronuclei showed mismatched H2B signals, a figure the authors note is an underestimate since same-color transfers are invisible to this assay. Transfer frequency was density-dependent and was completely abolished by a 4-μm pore transwell filter that prevented physical cell-cell contact, confirming the contact-dependent nanotube mechanism.

The nanotubes themselves were characterized as microtubule-rich structures (positive for α-tubulin), distinct from chromatin bridges arising from dicentric chromosomes. Average DNA transport speed within nanotubes was measured at ~390 nm/min. Plasma membrane labeling with CAAX-Halo confirmed that cargo traversed genuine membrane-enclosed nanotube connections. Approximately 26.7% of transferred micronuclei retained Lamin B1 coating, while the remainder were uncoated — indicating both lamina-enclosed and bare cytoplasmic DNAs can be transferred.

Most strikingly, transferred DNA was not merely a passive passenger — it was functionally integrated. Transferred fragments were stably inherited across multiple cell generations as extrachromosomal genetic elements. In a proof-of-concept experiment, the team demonstrated that DNA encoding drug resistance genes was transferred from donor to recipient cells, which subsequently acquired heritable resistance to the corresponding drug — a de novo phenotypic change conferred entirely by horizontal-like DNA transfer. This positions nanotube-mediated DNA transfer as a previously unrecognized mechanism of non-cell-autonomous genome reshaping in mammals, with potential relevance to cancer evolution, tissue aging, and disease progression.