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Molecular and Cellular Biology, September 2005, p. 7780-7795, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7780-7795.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Multiple Fates of L1 Retrotransposition Intermediates in Cultured Human Cells{dagger}

Nicolas Gilbert,1,2* Sheila Lutz,1 Tammy A. Morrish,1 and John V. Moran1*

Departments of Human Genetics and Internal Medicine, 1241 E. Catherine St., University of Michigan Medical School, Ann Arbor, Michigan 48109-0618,1 INSERM, Institut de Génétique Humaine, UPR 1142, 141 rue de la Cardonille, 34396 Montpellier cedex 5, France2

Received 17 March 2005/ Returned for modification 11 April 2005/ Accepted 1 June 2005

LINE-1 (L1) retrotransposons comprise ~17% of human DNA, yet little is known about L1 integration. Here, we characterized 100 retrotransposition events in HeLa cells and show that distinct DNA repair pathways can resolve L1 cDNA retrotransposition intermediates. L1 cDNA resolution can lead to various forms of genetic instability including the generation of chimeric L1s, intrachromosomal deletions, intrachromosomal duplications, and intra-L1 rearrangements as well as a possible interchromosomal translocation. The L1 retrotransposition machinery also can mobilize U6 snRNA to new genomic locations, increasing the repertoire of noncoding RNAs that are mobilized by L1s. Finally, we have determined that the L1 reverse transcriptase can faithfully replicate its own transcript and has a base misincorporation error rate of ~1/7,000 bases. These data indicate that L1 retrotransposition in transformed human cells can lead to a variety of genomic rearrangements and suggest that host processes act to restrict L1 integration in cultured human cells. Indeed, the initial steps in L1 retrotransposition may define a host/parasite battleground that serves to limit the number of active L1s in the genome.

* Corresponding author. Mailing address for John V. Moran: Departments of Human Genetics and Internal Medicine, 1241 E. Catherine St., University of Michigan Medical School, Ann Arbor, MI 48109-0618. Phone: (734) 615-0456. Fax: (734) 763-3784. E-mail: moranj{at}umich.edu. Mailing address for Nicholas Gilbert: INSERM, Institut de Génétique Humaine, UPR 1142, CNRS, 141 rue de la Cardonille, 34396 Montpellier cedex 5, France. Phone: 33 (0) 4 99 61 99 47. Fax: 33 (0) 4 99 61 99 01. E-mail: Nicolas.Gilbert{at}igh.cnrs.fr.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2005, p. 7780-7795, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7780-7795.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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