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Nov 21, 2013

Proteomics System Catches Jumping Genes in the Act

  • To complete the various stages of their gymnastic routines, jumping genes rely on host factors, which are usually uncooperative or even hostile. Accordingly, jumps are rare and difficult to study. Even if a host factor were more inclined to “spot” a jumping gene than wrestle it to the mat, the jumping gene would insert itself so adroitly that the interaction would be easy to miss—presenting yet another difficulty to any scientist hoping to follow the jumping gene’s acrobatics.

    Both difficulties—the rarity of jumps and their fleeting nature—have been overcome by proteomics researchers. These researchers induced lab-grown human cells to express large amounts of jumping gene proteins. Doing so resulted in the formation of ribonucleoprotein (RNP) complexes—crouched, ready-for-action assemblies consisting of the jumping gene, its proteins, and RNA. Next, the researchers used a quick-freeze/cryomilling extraction technique to preserve RNP-host protein interactions, the better to identify which host proteins thwart the jumping genes, and which assist them.

    The induction and extraction techniques, refined by scientists representing Johns Hopkins University and The Rockefeller University, are described in a paper entitled “Affinity Proteomics Reveals Human Host Factors Implicated in Discrete Stages of LINE-1 Retrotransposition.” According to study leader Lixin Dai, Ph.D., a postdoctoral associate at Johns Hopkins, the combination of induction and extraction is “a good way of preserving the interactions.”

    Published November 21 in Cell, the paper identifies 37 host proteins that appeared to interact with the RNP complexes, and highlights two representative proteins—UPF1, which seemed to suppress gene jumping; and PCNA, which seemed to help it along.

    The “LINE-1” in the paper’s title refers to long interspersed element-1, or L1, an unusually successful jumping gene, in evolutionary terms. It has been such a successful self-replicator that it now accounts for up to 20% of the human genome. Quieter now, tamped down by host defenses, it can still be coaxed into action, at least in culture, as the researchers from Johns Hopkins and Rockefeller have demonstrated.

    In their paper, these researchers, besides identifying high-confidence protein interactors and detailing L1-RNP links with PCNA and UPF1, describe how they used in-cell imaging to reveal the existence of “at least three types of compositionally and functionally distinct L1 RNPs.”

    Reflecting on the implications of their findings, the authors write, “physical interactions between L1 proteins and host factors likely reflect a longstanding evolutionary battle between the parasite, which exploits opportunities to proliferate, and the host, which fights to suppress L1 accumulation. Dissecting the dynamics of this L1-host ‘arms race’ will help to better decipher our genome dynamics in relation to cancer, brain development, reproduction, and potentially to other human diseases.”



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