Under normal circumstances, the mammalian genome is protected within the safe boundaries of the interphase nucleus, and the stability of cellular functions is maintained by this spatial separation. However, genomic instability caused by factors such as cell division errors or DNA damage can trigger the leakage of nuclear DNA into the cytoplasm as micronuclei (abnormal nuclear structures that fail to integrate into the main nucleus during cell division) or chromosomal fragments. Beyond the autonomous signaling pathways initiated within the cell itself, the effects of these cytoplasm-exposed nuclear components on neighboring cells and the role of genomic information in intercellular dynamics constitute a significant area of research in modern molecular biology and cancer biology.
While it has long been known that this genomic material accumulating in the cytoplasm is eliminated by the cell’s autonomous protection mechanisms or that intracellular damage detection systems are activated, whether these damaged DNA fragments can be directly transferred to neighboring cells and cause permanent cellular changes has remained a significant knowledge gap in the biological world. The ability of cells to exchange various cytoplasmic contents, such as mitochondria and RNA, through structures called nanotubes has been previously demonstrated; however, it had not been shown whether nuclear-derived DNA components are subject to a similar transfer mechanism. Researchers aimed to test whether this abnormal cytoplasmic DNA state created by genomic instability allows for a permeable state that facilitates the direct horizontal transfer of genetic material between cells.
Within the scope of the study, to prevent cellular migration, cell nanotubes were made visible using cytochalasin D, a chemical that suppresses actin polymerization, and DNA movements were monitored using live-cell imaging techniques and fluorescent labeling strategies. To induce genomic instability, mitotic spindle toxins were applied to diploid human retinal pigment epithelial cells (RPE-1) and renal proximal tubule epithelial cells (RPTEC); furthermore, different DNA damage methods, such as targeted chromosome breaks via the CRISPR-Cas9 system and ionizing radiation applications, were integrated. To verify the stability and functionality of the transferred genetic material in the recipient cell genome, the transfer of the Y chromosome-linked antibiotic resistance gene (neoR) from male donor cells to female recipient cells was analyzed at the molecular level using selective culture media growth, single-cell RNA sequencing (scRNA-seq – an analysis method that determines the gene expression levels of individual cells), and dCas9-SunTag (an artificial protein system that fluorescently labels target DNA regions) reporter systems.
The investigations revealed that cytoplasmic DNA fragments are transferred to neighboring cells at an average speed of 390 nm/min via tunneling nanotubes, which are formed as a result of direct contact between cells and consist of microtubule-based cytoskeleton components. In cell analyses treated with mitotic inhibitors, it was determined that 1.1% to 3.9% of micronuclei migrated to the recipient cell, and the recipient cell integrated these foreign DNA fragments into its own chromosomal structure during mitosis following the interphase stage. In long-term selection experiments, it was confirmed that the neomycin resistance gene transferred from donor cells via nanotubes is stably maintained in recipient cells in the form of extrachromosomal circular DNA (ecDNA – genetic elements that exist independently of nuclear chromosomes and can replicate), actively transcribed and converted into functional proteins, thus associating the initially susceptible recipient cell population with an inherited drug resistance phenotype.
This study points to the existence of a previously unidentified horizontal gene transfer mechanism in mammalian cells, similar to bacterial conjugation. The findings suggest that somatic aneuploidy (a condition where the chromosome number in cells deviates from normal multiples) and DNA copy number variations may result not only from intracellular division errors but also from the intercellular exchange of genetic material. Based on the researchers’ data, the possibility that cancer cells with unstable genomic structures can transfer oncogenic alleles and resistance genes to neighboring normal or transformed cells via nanotubes has taken its place in the scientific literature as a noteworthy mechanism in tumor biology.
Translated by: Nehir Necem Ünlü
Editor: Elinsu Ak
Referans: Maurais, E. G., Mazzagatti, A., Lin, Y. F. et al. Genome instability triggers intercellular DNA transfer between human cells. Cell (2026). https://doi.org/10.1016/j.cell.2026.04.041
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