21 January 2009

The gene parasite is trimerized to attack human DNA

Nadezhda Markina, Infox.ruMolecular biologists from the Max Planck Institute for Developmental Biology in Tübingen, Germany, have figured out how the "genomic parasite" — the LINE-1 retrotransposon works.

This is a mobile genetic element with a length of about 6 thousand base pairs, which multiplies, moves along the DNA chain and is embedded in it in different places. It behaves like a real parasite, since it spoils the genetic code in the places of embedding and can change the work of surrounding genes. But, in addition to unpredictable consequences for the body, retrotransposons provide genetic variability, which serves as a necessary condition for evolution.

A parasite similar to a virus

The scheme of action of the retrotransposon is as follows. After the parasite is embedded in DNA, it encodes two enzymes — reverse transcriptase and integrase. Reverse transcriptase is an enzyme that builds DNA from an RNA matrix (the reverse of what happens during protein synthesis). With the help of retrotransposon RNA, new copies of DNA are produced. And the integrase enzyme embeds these copies into the genome. A retrotransposon has features similar to a virus: it multiplies and is embedded in the host genome, but unlike a virus, it cannot move from one cell to another.

In the human genome, approximately 17% of DNA carries the retrotransposon LINE-1 (long interspersed nuclear element 1). "Such a massive integration of the retrotransposon into the genome could not remain without consequences for human evolution," says Oliver Weichenrieder, a leading specialist in crystallography. "Nevertheless, we still know very little about the mechanisms of its reproduction and introduction into the genome, as well as about the molecules involved in this process."

Self-replicating device

Biologists learned the role of molecules through the study of their structure. Oliver Weichenrieder and Elena Khazina have deciphered the crystal structure of one of the two proteins encoded by the human retrotransposon LINE-1. This protein L1ORF1p is exactly the reverse transcriptase enzyme that attaches to the retrotransposon RNA and builds DNA from its matrix. And in this way multiplies the genetic parasite.

It turned out that the L1ORF1p protein consists of three parts. The first one, in fact, is responsible for the fact that three protein molecules combine and form a functionally active trimer. The other two parts of each of the combined molecules provide the connection of protein with RNA. Elena Khazina considers the most important discovery to be the recognition of the crystal structure of the RRM domain (RNA Recognition Motif), which recognizes RNA. The domain has an extended loop stabilized by salt bridges.

The discovery of the structure of this domain allowed scientists to understand how the human retrotransposon LINE-1 reproduces and moves. But not only that. They also found the RRM domain in retrotransposons that parasitize the genomes of various animals and plants. Apparently, this domain is necessary in any situation where it is required to bind protein to RNA.

The LINE-1 retrotransposon not only reproduces itself, but is also responsible for the integration of other parasitic sequences (Alu sequences) into the genome. They are found only in higher primates and occupy about 10% of the genome of humans and great apes. Apparently, retrotransposons have played a significant role in the evolution of our genome, the authors say.

You can learn from genetic parasites

The work of molecular biologists is not only purely scientific, but also of practical interest. Scientists believe that a mechanism can be borrowed from retrotransposons to accurately embed the desired genetic structure in DNA for gene therapy purposes. This is a much more precise mechanism than the viral constructs currently in use.

The article by Elena Khazina and Oliver Weichenrieder Non-LTR retrotransposons encode noncanonical RRM domains in their first open reading frame is published in the journal Proceedings of the National Academy of Sciences.

Portal "Eternal youth" www.vechnayamolodost.ru21.01.2009

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