The Cell and its Nucleus on a human scale – VI — untwisting the linguini

Recall that the 150 foot sphere sitting on the 50 yardline contains some 15,000,000 feet of twisted linguini (DNA).  The two strands are 3/8th of an inch thick.  They twist around each other every 9/16ths of an inch.  We now have the problem separating the two strands to transcribe one of them into messenger RNA (mRNA) so the ribosome can make protein from the mRNA.  The RNA is single stranded.  The machine which accomplishes transcription is RNA polymerase II (see for more detail).  We’re going to essentially forget chemistry at this point and just consider what must occur physically when this happens.

At this point, since word pictures can only go so far,  get two pieces of string each about 1/8th of an inch thick — say a bass guitar string, and wrap them around each other 20 – 50 times, approximating our linguini.  Staple both ends down to some wood. Now start in the middle of the strings, and separate the two strands by a few turns using a pencil.  RNA polymerase must actually do this to copy one strand of DNA into RNA.   You will quickly see that the string knots up in front of the separated parts.  Now imagine moving the separated part forward — the knots get worse.  The DNA (and the strings) respond by forming supercoils — hard to draw but easy to see if you have string in front of you.  The supercoils are called positive (overwound) in front of the separated part and negative (underwound) behind it.

Now of course the ends of DNA aren’t fixed in the cell, but they might as well be, because even the shortest chromosome (#21) is 46 miles long, with a twist every 9/16ths of an inch (in the linguini model at least).  The solution is an ingenious family of enzymes called topoisomerases.   They cut either one or both strands of DNA, allowing the overwound sections to unravel, and the underwound sections to tighten up.  After this happens topoisomerases hook the broken strands back together.  Such a type of enzyme must have been present at very early times, when life began to use double stranded DNA (or double stranded RNA for that matter).  How double stranded DNA could have coded for something absolutely required to allow double stranded DNA to be transcribed into anything, I’ll leave to the ‘it all happened by chance, and with natural selection producing incremental improvement’ boys.  I don’t have a clue, and regard the existence of topoisomerase as rather miraculous.

Now it’s time to consider the size of RNA polymerase II.  It’s much larger in man than bacteria.  Even in bacteria it’s much larger than width of the double helix.  The longest part is 7 times the diameter of the helix and the other axes are 5 – 6 times larger.  The transcription rate is around 3 kiloBases/minute or a transcription rate  of an additional nucleotide to the growing chain every 20 milliSeconds.  So every 5th of a second it has transcribed a complete turn of the helix, merrily inducing coiling upstream and downstream.  It’s pretty clear that it’s the DNA which must move rather than the polymerase, as the polymerase is so much larger than the DNA it’s working on.

In our model the polymerase is only moving 50 * 1/16 of an inch per second or about 3 inches a second — we should be able to see that.  We should be able to see the polymerase as well as it’s 4 inches long in its longest part.

Lastly, consider the nucleosome which most of the DNA is wrapped around.  It’s still far from clear just how the 4 inch polymerase can move around the two turns of DNA wrapped twice around a nucleosome 2 inches in diameter and an inch high, separating the strands and copying one of them as it goes.  Perhaps the nucleosome is displaced and then quickly reforms after the polymerase passes.

When you consider what’s really going on inside us all the time, it’s hard to imagine that this works flawlessly enough to allow us to live.  The more you know about molecular biology, the more miraculous life becomes, not less.

Finally, a rest in peace to my late friend Nick Cozzarelli, gone far too soon, who did seminal work on the topoisomerases.

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