Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres.
In: Nature, Jg. 446 (2007-03-08), Heft 7132, S. 208-212
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Zugriff:
Long interspersed element-1 (LINE-1 or L1) elements are abundant, non-long-terminal-repeat (non-LTR) retrotransposons that comprise ∼17% of human DNA. 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 transcription. 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 repair. 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 ends. 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. [ABSTRACT FROM AUTHOR]
Titel: |
Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres.
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Autor/in / Beteiligte Person: | Morrish, Tammy A. ; Garcia-Perez, José Luis ; Stamato, Thomas D. ; Taccioli, Guillermo E. ; Sekiguchi, Jo ; Ann ; Moran, John V. |
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Zeitschrift: | Nature, Jg. 446 (2007-03-08), Heft 7132, S. 208-212 |
Veröffentlichung: | 2007 |
Medientyp: | academicJournal |
ISSN: | 0028-0836 (print) |
DOI: | 10.1038/nature05560 |
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