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Peer-reviewedCC BY-NC-NDNature Communications

LINE-1 insertion intermediates recombine with one another or with DNA breaks to form genome rearrangements

  • Carlos Mendez‐Dorantes1,2,3
  • Jupiter C. Kalinowski4,5
  • Aidan Burn4,5
  • Phillip Schofield4,5
  • Cheuk‐Ting Law4,5,6
  • Esin Işık4,5,6
  • Kathleen H. Burns7,8,9
9 affiliations
  1. 1Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. [email protected]
  2. 2Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected]
  3. 3Department of Pathology, Harvard Medical School, Boston, MA, USA. [email protected]
  4. 4Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
  5. 5Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA
  6. 6Department of Pathology, Harvard Medical School, Boston, MA, USA
  7. 7Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. [email protected]
  8. 8Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected]
  9. 9Department of Pathology, Harvard Medical School, Boston, MA, USA. [email protected]
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Abstract

LINE-1 retrotransposition is common in human cancers and rearrangements at insertion sites can contribute to cancer-driving oncogene amplifications and promote genome instability. However, the mechanisms underlying rearrangements of L1 retrotransposition intermediates are poorly understood. To address this gap, we developed GFP-based recombination reporter assays to study the formation of L1 retrotransposition-mediated rearrangements. Using these reporters combined with long-read sequencing approaches, we find that L1 retrotransposition intermediates can recombine with distal DNA breaks to generate chromosomal rearrangements. We also find that two distinct L1 insertion intermediates can recombine with each other to generate chromosomal rearrangements. Both types of rearrangements depend on L1-encoded ORF2p endonuclease and reverse transcriptase activities. Using these reporters, we discover that L1 retrotransposition-mediated rearrangements are robustly induced when the recombining sequences share homology and that their formation requires the homologous recombination factor BRCA1. Given the repetitive nature of our genome, these findings highlight the risk of L1 insertion intermediates becoming substrates for aberrant recombination and promoting genome instability.

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Cite

BibTeXRIS
BibTeX
@article{mendezdorantes2026line1,
  title = {{LINE-1 insertion intermediates recombine with one another or with DNA breaks to form genome rearrangements}},
  author = {Carlos Mendez‐Dorantes and Jupiter C. Kalinowski and Aidan Burn and Phillip Schofield and Cheuk‐Ting Law and Esin Işık and Kathleen H. Burns},
  journal = {Nature Communications},
  year = {2026},
  month = aug,
  doi = {10.1038/s41467-026-76308-7},
  url = {https://doi.org/10.1038/s41467-026-76308-7},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - LINE-1 insertion intermediates recombine with one another or with DNA breaks to form genome rearrangements
AU  - Carlos Mendez‐Dorantes
AU  - Jupiter C. Kalinowski
AU  - Aidan Burn
AU  - Phillip Schofield
AU  - Cheuk‐Ting Law
AU  - Esin Işık
AU  - Kathleen H. Burns
PY  - 2026
DA  - 2026/08/01
JO  - Nature Communications
DO  - 10.1038/s41467-026-76308-7
UR  - https://doi.org/10.1038/s41467-026-76308-7
AB  - LINE-1 retrotransposition is common in human cancers and rearrangements at insertion sites can contribute to cancer-driving oncogene amplifications and promote genome instability. However, the mechanisms underlying rearrangements of L1 retrotransposition intermediates are poorly understood. To address this gap, we developed GFP-based recombination reporter assays to study the formation of L1 retrotransposition-mediated rearrangements. Using these reporters combined with long-read sequencing approaches, we find that L1 retrotransposition intermediates can recombine with distal DNA breaks to generate chromosomal rearrangements. We also find that two distinct L1 insertion intermediates can recombine with each other to generate chromosomal rearrangements. Both types of rearrangements depend on L1-encoded ORF2p endonuclease and reverse transcriptase activities. Using these reporters, we discover that L1 retrotransposition-mediated rearrangements are robustly induced when the recombining sequences share homology and that their formation requires the homologous recombination factor BRCA1. Given the repetitive nature of our genome, these findings highlight the risk of L1 insertion intermediates becoming substrates for aberrant recombination and promoting genome instability.
SN  - 2041-1723
ER  -