A fundamental mechanism of intracellular defence against jumping genes has been elucidated in human cells

"Jumping genes" can cause genetic disorders and can be involved in the development of tumours. Researchers at the Paul-Ehrlich-Institut have succeeded in elucidating a previously unknown mechanism used by human cells to keep these endogenous retrotransposons in check. A member of the so-called APOBEC3 protein family plays a central role here. This protein family also protects humans from the proliferation of pathogenic viruses. In its online edition of 7 October 2013, Nucleic Acids Research reports on the research results.

A group of mobile genetic elements duplicates and proliferates to different sites of the human genome using a ‘copy & paste’ mechanism. In favourable cases, these so-called retrotransposons bring about genetic modifications which present an evolutionary advantage. However, they can also cause genetic disorders or become involved in tumour development. Human cells do not take this lying down: They block the mobilisation of these endogenous transposable elements by means of various intracellular defence mechanisms. Only few of these protective mechanisms have so far been fully understood. However, it is known that an enzyme of the APOBEC3 protein family, the cytidindeaminase APOBEC3C, plays an important part. This protein is also involved in the intracellular defence against pathogenic viruses. APOBEC3C has been found in nearly all cell types and tissues which have so far been examined for its presence.

Human cell in which the LINE-1 protein machinery (red) and the APOBEC3C proteins which are required for intracellular defense (green) are accumulating in the same regions (yellow) outside the nucleus (blue). Source: PEI

Professor Gerald Schumann, Division Medical Biotechnology, and his co-workers have shown in previous studies that the activity of the human LINE-1 (Long Interspersed Element-1) and Alu retrotransposons can be restricted by up to 75 percent via APOBEC3C. [1,2]. Now, they have investigated the mechanism that is responsible for APOBEC3C-mediated LINE-1 inhibition. In the course of their research, they established that it is not the cytidindeaminase activity which is responsible, but rather the interaction between a ribonucleic acid (RNA), APOBEC3C proteins and a LINE-1 encoded protein that leads to a spatial blockage of the enzyme reverse transcriptase (RT), which is also part of the LINE-1 protein machinery. For this reason, the RT is no longer able to decode the genetic information efficiently. This blockage prevents both copying and insertion of the jumping genes.

"This is the first time, a mechanism of LINE-1 restriction by a member of the APOBEC3 protein family has been elucidated", explained Professor Gerald Schumann and, to complete his statement, he said: "Maybe this mechanism can be used to protect therapeutically relevant cells from the uncontrolled and damaging activities of mobile genetic elements by means of overexpression of APOBEC3C."

Original publication

DOI:10.1093/nar/gkt898

Horn AV, Klawitter S, Held U, Berger A, Vasudevan AA, Bock A, Hofmann H, Hanschmann KM, Trösemeier JH, Flory E, Jabulowsky RA, Han J, Löwer J, Löwer R, Münk C, Schumann GG (2014): Human LINE-1 restriction by APOBEC3C is deaminase independent and mediated by an ORF1p interaction that affects LINE reverse transcriptase activity.
Nucleic Acids Res 42: 396-416.
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References:

1. Muckenfuss H et al. (2006). APOBEC3 proteins inhibit human LINE-1 retrotransposition. J. Biol. Chem. 281: 22161-22172.
2. Schumann GG et al. (2010). Unique functions of the repetitive transcriptome. Int. Rev. Cell. Mol. Biol. 285: 115-188.