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Yet Another Face of DNA

Stephen L. Talbott

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Posted: September 29, 2013   (Article 11)

One of the unquestioned certainties of the human genome has long been that nearly all cells in our bodies contain identical DNA. (Some cancerous tissues and certain immune cells are major known exceptions.) Another truth has seemed so evident as to require little explicit statement: DNA knows its proper place in the cell, and stays there. Yet on both counts the reigning convictions have turned out to be more than a little shaky. And on both counts the emerging evidence testifies to yet more things the organism does to manage its own genome.

In a previous posting I reported on our “genetically mosaic” bodies, describing how different groups of cells or tissues in the same body possess somewhat different genomes. This, of course, contravenes a long-running assumption about the overall genetic uniformity of the organism. There was supposed to be just one “plan” (or “recipe” or “Book of Life”), not many variants of it. If there are different versions of the plan, then either biologists will be sent on a fruitless search for a distinct “master plan” that “controls” the relations between the subordinate plans, or (one rather hopes) they will begin to give more credence to the agency of the organism itself as a living whole — the organism they already incessantly speak of as a thoughtful agent.

Here I will add something about the refusal of DNA to stay where it “belongs”. Indeed, the remarkable thing is that DNA, so often viewed as an endpoint of cell signaling, has now been found to look suspiciously like a signaling molecule itself. Or, at least, fragments of it do.

Genomic wanderlust

It’s been known for at least a few years that bits of DNA can be found outside the cell and are even transferred to different parts of the body. Such findings tend to be dismissed early on as meaningless — the result of cellular “mistakes” or random noise without biological function. But now a team of Chinese and American molecular biologists (Cai et al.*) has produced some rather startling evidence.

They discovered at least 16,434 genomic DNA (gDNA) fragments in human blood plasma. These “donor” fragments were double-stranded DNA generally running 6000 – 17,000 “letters”, or nucleotide bases, in length. They showed themselves capable of entering the cytoplasm and nuclei of recipient cells. The particular fragments dealt with in this study were transported within extracellular vesicles — small, membrane-bound “containers” budding off from the donor cell membrane and carrying a cargo of signaling molecules and other contents that can subsequently be absorbed into other cells.

(There is a whole story — or, rather, a group of stories — to be told about the role of the cell membrane, together with the various molecules embedded in it and acting upon it, in regulating all this — that is, in regulating the incorporation of “proper” vesicle contents and then detaching the vesicle from the larger membrane. And, of course, following detachment there remains the big question, “Where should we go now, and what processes in the larger organism should we participate in?”)

Having verified that the gDNA entered the nuclei of other cells, the researchers asked themselves whether it could then function along with the recipient cell’s native DNA. In particular, could the nomadic fragments produce messenger RNAs that are then translated into protein? And would this protein affect the cell’s functioning? Their answer to these questions was a resounding “yes”:

[The] gDNAs in extracellular vesicles are transportable between the same or different types of cells, increase the gDNA-[encoded] mRNA and protein expressions in the recipient cells, and have physiological significance to influence function in recipient cells. ... Our present study provides direct evidence that transferred gene[s] can be transcribed in the recipient cells.

The authors add that “secreted DNA may represent a class of signaling molecules that may play an important role in mediating intercellular communication. Moreover, the selective secretion and targeting of DNA among different cells provide a highly regulated complex network under various physiological and pathophysiological conditions”.

So we have bits of DNA undertaking adventures not only outside the nucleus, but altogether outside the cell, on their way to distant shores and subject to remote influences! Yet the picture meshes well with all the other ways the organism seamlessly integrates its genome with the many-faceted processes of its own life. A “highly regulated complex network”, distributed throughout the body, subject to “physiological conditions” and involving the “selective secretion and targeting of DNA among different cells” hardly sounds like a mechanism under centralized control.

Functional possibilities

What roles do these itinerant DNA fragments play within the organism? One suggestion (by neuroscientists John Smythies and Lawrence Edelstein*) is that they act as “jumping genes” (transposons) — except that whereas transposons are stretches of DNA that “jump” from place to place within the chromosomal complement of a single cell or else jump between organisms, as when viruses insert portions of their DNA into the host organism’s chromosomes, these new, ambulatory DNA fragments move from cell to cell within a single organism. This could give the organism remarkable powers for remodeling its own genome.

Some researchers have proposed that the fragments may help to repair damaged DNA in recipient cells, and have demonstrated this actually happening in experimental setups. And there have been other suggestions as well.

As with virtually every aspect of the cell, increasing study of extracellular DNA fragments is producing an ever more complex story. These fragments can occur in a free and soluble form, or in particulate form, where they are complexed with proteins and lipids. They may or may not be associated with microvesicles. A complex called the “virtosome” contains not only DNA, but also RNA and, intriguingly, it incorporates the enzymes that replicate DNA and transcribe it into RNA (Peters and Pretorius*). There are indications that the release of DNA fragments is regulated and also cell-type-specific. For example, the prostate gland has been shown to secrete vesicles containing DNA fragments along with prostate-specific membrane antigens (substances that stimulate the generation of antibodies as part of an immune response).

As a further indication of their significance, extracellular DNA fragments, like virtually all aspects of the organism, can play a role in disease. This is true of at least some cancers. For example, leukemic cells in the bone marrow can release DNA fragments into the surrounding microenvironment, undermining the stability of certain cells and facilitating tumor progression (DvoÅáková et al.*).

We are hardly yet in a position to imagine the potential range of significant activities involving genomic DNA fragments. But the possibilities become endless once you have DNA segments moving around between cells in the body. For example, this could take the idea of the genomically mosaic organism, discussed in my post of August 22, 2013, to a whole new level — as perhaps also the protein-centric (rather than DNA-centric) view of the organism discussed in the August 2, 2013 post. It is, after all, proteins that must (in cooperation with many other molecules, of course) see to the adventures of this movable DNA, from its initial production to its final incorporation into the chromosome of another cell.

Tags: signaling; DNA

Sources: Cai, Jin, Yu Han, Hongmei Ren et al. (2013). “Extracellular Vesicle-Mediated Transfer of Donor Genomic DNA to Recipient Cells is a Novel Mechanism for Genetic Influence Between Cells”, Journal of Molecular Cell Biology vol. 5, pp. 227-38. doi:10.1093/jmcb/mjt011

DvoÅáková, M., V. Karafiát, P. Pajer et al. (2012). “DNA Released by Leukemic Cells Contributes to the Disruption of the Bone Marrow Microenvironment”, Oncogene. doi:10.1038/onc.2012.553

Peters, Dimetrie L. and Piet J. Pretorius (2011a). “Origin, Translocation and Destination of Extracellular Occurring DNA — A New Paradigm in Genetic Behavior”, Clinica Chimica Acta vol. 412, pp. 806-11. doi:10.1016/j.cca.2011.01.026

Smythies, John and Lawrence Edelstein (2013). “Interactions Between the Spike Code and the Epigenetic Code During Information Processing in the Brain”, Frontiers in Molecular Neuroscience vol. 6, article 17 (July). doi:10.3389/fnmol.2013.00017

Further information: For a broad sketch of the range of regulatory processes the organism brings to bear upon its DNA, see the extensive collection of notes from the technical literature entitled How the Organism Decides What to Make of Its Genes

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Steve Talbott :: Yet Another Face of DNA