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Nucleic Acids Research Advance Access originally published online on July 10, 2007
Nucleic Acids Research 2007 35(14):4914-4926; doi:10.1093/nar/gkm516
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Nucleic Acids Research, 2007, Vol. 35, No. 14 4914-4926
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural Biology

Determinants for DNA target structure selectivity of the human LINE-1 retrotransposon endonuclease

Kostas Repanas1, Nora Zingler2, Liliana E. Layer2, Gerald G. Schumann2, Anastassis Perrakis1 and Oliver Weichenrieder1,*

1Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands and 2Paul-Ehrlich-Institut, Section PR2/Retroelements, 63225 Langen, Germany

*To whom correspondence should be addressed. Tel: +4970716011358; Fax: +4970716011353; Email: oliver.weichenrieder{at}tuebingen.mpg.de

Received April 12, 2007. Revised May 18, 2007. Accepted June 15, 2007.

The human LINE-1 endonuclease (L1-EN) is the targeting endonuclease encoded by the human LINE-1 (L1) retrotransposon. L1-EN guides the genomic integration of new L1 and Alu elements that presently account for ~28% of the human genome. L1-EN bears considerable technological interest, because its target selectivity may ultimately be engineered to allow the site-specific integration of DNA into defined genomic locations. Based on the crystal structure, we generated L1-EN mutants to analyze and manipulate DNA target site recognition. Crystal structures and their dynamic and functional analysis show entire loop grafts to be feasible, resulting in altered specificity, while individual point mutations do not change the nicking pattern of L1-EN. Structural parameters of the DNA target seem more important for recognition than the nucleotide sequence, and nicking profiles on DNA oligonucleotides in vitro are less well defined than the respective integration site consensus in vivo. This suggests that additional factors other than the DNA nicking specificity of L1-EN contribute to the targeted integration of non-LTR retrotransposons.

Present addressess: Nora Zingler, Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA Oliver Weichenrieder, Max-Planck-Institute for Developmental Biology, Department of Biochemistry, 72076 Tuebingen, Germany


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