Sunday, September 3, 2017

PIWI and Friends Fight Zombie DNA!

How tiny RNAs fight the good fight to keep mindless, selfish junk DNA from eating the rest of the genome.

Our genomes are full of junk. Only about 5 to 10% of it has any function at all. Not only is the rest junk, but over half of the genome is made up of transposable elements (also called transposons) in various states of mutational disrepair, mostly fossils and relics. These are selfish DNA "organisms" (about 6500 basepairs long) that when fully functional can reproduce by making copies which insert themselves elsewhere into the DNA. They are like zombies, mindless and simple, knowing nothing other than an implacable desire to reproduce by using the other machinery of the cell to attack the rest of genome with yet more copies of themselves, and continuing to do havoc even when partially diabled. This kind of thing can, naturally, be very damaging. That is why our germ cells have special protection through tiny RNAs called PIWI RNAs, or piRNAs.

piRNAs, at about 26 to 31 nucleotides in length, are even smaller than the transposable elements they defend against. In the typical case, they are encoded by one of thousands of clusters sprinkled around the genome. They are expressed mostly in the germ cells, where it is naturally of particular importance to keep transposons under control. After being processed to their mature size, they bind to partner proteins of the PIWI family forming a guided missile that finds the matching (i.e. complementary) sequence among other RNAs in the cell- those made by its target transposon- and destroys that RNA by chopping it up. We have tens of thousands of these piRNAs, and if their action is inactivated, transposons start jumping around at a hundred-fold the normal rate, and the sperm (this is usually studied in males) is infertile, because of all the damage, though also because of other roles piRNAs have in this process.

Where did this mechanism come from? It seems to be quite ancient, as is the race between parasitic DNA elements and cellular organisms. Sponges have them, and all eukaryotes even prior to animals all have the related miRNA systems which also act to cut up or down-regulate target RNA messages. How did we accumulate so much piRNA, on the order of 6,000 clusters encoding hundreds of thousands of individual units in our genome? That was doubtless driven by the promiscuous and persistent nature of the transposable elements they are fighting against, via natural selection. But do piRNA genes develop directly from transposons in some fashion? Otherwise, the cost from randomly mutating and hitting other parts of the genome by mistake could be quite high.

Indeed, there is something called a ping-pong mechanism that generates extra piRNAs from the remaining fragments of piRNA-cleaved transposon mRNAs. This helps finish the job of defense, but whether such piRNAs can somehow lead, even rarely, to extra units of genomic piRNA, via reverse transcription or other means, is yet unkown. What is known is that the clusters from which piRNAs are expressed are graveyards of old, defunct transposons. These regions seem to be specially marked in the chromosome, in ways again dependent on the piRNA system, so that they get transcribed and processed into piRNAs, rather than other things.

Basic cycle of piRNA production, action, and ping-pong propagation. After production and processing, short piRNAs (red), docked to their PIWI protein partners (Aub), direct the cleavage and destruction of transposable element RNA (blue). Some of the resulting pieces dock with another PIWI protein (Ago3), and get likewise processed to repeat the cycle on the complementary strand, which repeats again, etc. This makes the accuracy of the original targeting critically important, of course.

To do this, piRNAs have another role, which is to direct methylation of the DNA, setting up specialized chromatin zones. While all the other defensive operations of the piRNAs have been in the cytoplasm, this takes place in the nucleus, using different PIWI-related proteins. This process targets transposons as well as the related piRNA-generating clusters, and has a two-fold point. In the first place, it strongly represses normal transcription from transposons, another form of direct defense. Secondly, it seems to switch these regions into the piRNA mode of production, where altered transcription, which is not very well understood yet, generates the long piRNA precursors (rather than the transposon messages) and initiates their processing.

As if that were not all, piRNAs are sprinkled around the rest of the genome in normal genes, which they help to regulate. At later steps of sperm production, after the major role of defense against transposable elements has passed, this other class of piRNAs destroy most of the remaining cellular mRNA, to streamline the cell down to only the essentials. How this dramatic event is controlled and restricted to these times is not understood, however.

There is a great deal more to be said and investigated about this genomic quasi-immune system. However it is already clear that it is a critically important process that mobilizes massive resources, in a quiet arms race that we are running against persistent and ancient enemies that lurk within.

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