Chromosomal rearrangements and instability caused by the LINE-1 retrotransposon

Mendez-Dorantes, C.; Zeng, X.; Karlow, J. A.; Schofield, P.; Turner, S.; Kalinowski, J.; Denisko, D.; Lee, E. A.; Burns, K. H.; Zhang, C.-Z.

doi:10.1101/2024.12.14.628481

bioRxiv · 10.1101/2024.12.14.628481

Chromosomal rearrangements and instability caused by the LINE-1 retrotransposon

Mendez-Dorantes, C.·Zeng, X.·Karlow, J. A.·Schofield, P.·Turner, S.·Kalinowski, J.·Denisko, D.·Lee, E. A.·Burns, K. H.·Zhang, C.-Z.

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Abstract

LINE-1 (L1) retrotransposition is widespread in many cancers, especially those with a high burden of chromosomal rearrangements. However, whether and to what degree L1 activity directly impacts genome integrity is unclear. Here, we apply whole-genome sequencing to experimental models of L1 expression to comprehensively define the spectrum of genomic changes caused by L1. Combining the analyses of experimental models of L1 induction and of cancer genomes, we demonstrate that L1 retrotransposition can directly generate reciprocal translocations, genomic DNA inversions, and foldback rearrangements resulting from illegitimate recombination of double-strand DNA ends generated by L1-encoded ORF2p. We further show that L1-induced rearrangements can produce unstable chromosomes that fuel the acquisition of complex rearrangements, large segmental copy-number alterations, and genetic heterogeneity through breakage-fusion bridge cycles or DNA fragmentation. Together, these findings suggest L1 as a potent mutagenic force capable of driving genome evolution in cancers.

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Mendez-Dorantes, C., Zeng, X., Karlow, J. A., Schofield, P., Turner, S., Kalinowski, J., Denisko, D., Lee, E. A., Burns, K. H., Zhang, C.-Z.. 2024-12-17. Chromosomal rearrangements and instability caused by the LINE-1 retrotransposon. https://doi.org/10.1101/2024.12.14.628481

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