Genome instability triggers intercellular DNA transfer between human cells

  • Cell. 2026 May 19:S0092-8674(26)00508-8. doi: 10.1016/j.cell.2026.04.041.
Elizabeth G Maurais  1 ,  Alice Mazzagatti  1 ,  Yu-Fen Lin  1 ,  Maria Narozna  2 ,  Qing Hu  3 ,  Rashmi Dahiya  1 ,  Derek Santiago-Ferrer  4 ,  Conor P Herlihy  5 ,  Mary Krebs  5 ,  Nikoleta Pateraki  6 ,  Evlampia Parcharidou  6 ,  Stamatis Papathanasiou  6 ,  Brian J Beliveau  7 ,  Gary J Gorbsky  8 ,  Isidro Cortés-Ciriano  9 ,  Peter Ly  10
Affiliations
  • 1. Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2. Cell Cycle and Cancer Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
  • 3. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4. Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 5. Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • 6. Institute of Molecular Biology, 55128 Mainz, Germany.
  • 7. Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA.
  • 8. Cell Cycle and Cancer Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Department of Cell Biology, University of Oklahoma Health Campus, Oklahoma City, OK 73104, USA.
  • 9. European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK; Somatic Genomics Programme, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
  • 10. Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Harold C. Simmons Comprehensive Cancer Center, Department of Cell Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
PMID: 42161273 DOI: 10.1016/j.cell.2026.04.041
Abstract

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.

Keywords
DNA damage; chromothripsis; cytoplasmic DNA; ecDNA; genomic instability; horizontal gene transfer; intercellular transfer; micronuclei; mitosis; tunneling nanotubes.
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