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J. Biol. Chem., Vol. 281, Issue 31, 22161-22172, August 4, 2006

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APOBEC3 Proteins Inhibit Human LINE-1 Retrotransposition^*

Heide Muckenfuss¹, Matthias Hamdorf¹, Ulrike Held, Mario Perkovi, Johannes Löwer, Klaus Cichutek, Egbert Flory, Gerald G. Schumann², and Carsten Münk³

From the Division of Medical Biotechnology, Section Pr2/Retroelements, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, D-63225 Langen, Germany

The human cytidine deaminase family APOBEC3 represents a novel group of proteins in the field of innate defense mechanisms that has been shown to be active against a variety of retroviruses. Here we examined whether members of the APO-BEC3 family have an impact on retrotransposition of human long interspersed nuclear elements (LINE-1s or L1s). Using a retrotransposition reporter assay in HeLa cells, we demonstrate that in the presence of transiently transfected APOBEC3A, L1 retrotransposition frequency was reduced by up to 85%. Although APOBEC3G and -3H did not influence L1 retrotransposition notably, expression of APOBEC3B, -3C, and -3F inhibited transposition by 75%. Although reverse transcription of L1s occurs in the nucleus and APOBEC3 proteins are believed to act via DNA deamination during reverse transcription, activity against L1 retrotransposition was not correlated with nuclear localization of APOBEC3s. We demonstrate that APOBEC3C and APOBEC3B were endogenously expressed in HeLa cells. Accordingly, down-regulation of APOBEC3C by RNA interference enhanced L1 retrotransposition by 78%. Sequence analyses of de novo L1 retrotransposition events that occurred in the presence of overexpressed APOBEC3 proteins as well as the analyses of pre-existing endogenous L1 elements did not reveal an enhanced rate of G-to-A transitions, pointing to a mechanism independent of DNA deamination. This study presents evidence for a role of host-encoded APOBEC3 proteins in the regulation of L1 retrotransposition.

Received for publication, February 22, 2006 , and in revised form, May 19, 2006.

^* This work was supported in part by Deutsche Forschungsgemeinschaft Grant SCHU1014/5-2 (to G. G. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Both authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 49-6103-77-3105; Fax: 49-6103-77-1255; E-mail: schgr{at}pei.de.

³ To whom correspondence may be addressed. Tel.: 49-6103-77-4002; Fax: 49-6103-77-1255; E-mail: mueca{at}pei.de.

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