Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres

Tammy A. Morrish (), José Luis Garcia-Perez, Thomas D. Stamato, Guillermo E. Taccioli, JoAnn Sekiguchi and John V. Moran ()
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Tammy A. Morrish: and
José Luis Garcia-Perez: and
Thomas D. Stamato: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096, USA
Guillermo E. Taccioli: 80E Concord Street, Boston University School of Medicine, Boston, Massachusetts 02118-2526, USA
JoAnn Sekiguchi: and
John V. Moran: and

Nature, 2007, vol. 446, issue 7132, 208-212

Abstract: Abstract Long interspersed element-1 (LINE-1 or L1) elements are abundant, non-long-terminal-repeat (non-LTR) retrotransposons that comprise ∼17% of human DNA1. The average human genome contains ∼80–100 retrotransposition-competent L1s (ref. 2), and they mobilize by a process that uses both the L1 endonuclease and reverse transcriptase, termed target-site primed reverse transcription3,4,5. We have previously reported an efficient, endonuclease-independent L1 retrotransposition pathway (ENi) in certain Chinese hamster ovary (CHO) cell lines that are defective in the non-homologous end-joining (NHEJ) pathway of DNA double-strand-break repair6. Here we have characterized ENi retrotransposition events generated in V3 CHO cells, which are deficient in DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity and have both dysfunctional telomeres and an NHEJ defect. Notably, ∼30% of ENi retrotransposition events insert in an orientation-specific manner adjacent to a perfect telomere repeat (5′-TTAGGG-3′). Similar insertions were not detected among ENi retrotransposition events generated in controls or in XR-1 CHO cells deficient for XRCC4, an NHEJ factor that is required for DNA ligation but has no known function in telomere maintenance. Furthermore, transient expression of a dominant-negative allele of human TRF2 (also called TERF2) in XRCC4-deficient XR-1 cells, which disrupts telomere capping, enables telomere-associated ENi retrotransposition events. These data indicate that L1s containing a disabled endonuclease can use dysfunctional telomeres as an integration substrate. The findings highlight similarities between the mechanism of ENi retrotransposition and the action of telomerase, because both processes can use a 3′ OH for priming reverse transcription at either internal DNA lesions or chromosome ends7,8. Thus, we propose that ENi retrotransposition is an ancestral mechanism of RNA-mediated DNA repair associated with non-LTR retrotransposons that may have been used before the acquisition of an endonuclease domain.

Date: 2007
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DOI: 10.1038/nature05560

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